N-pyridinyl acetamide derivatives as Wnt signalling pathway inhibitors

ABSTRACT

Disclosed are compounds useful as inhibitors of the Wnt signalling pathway. Specifically, inhibitors of Porcupine (Porcn) are contemplated by the invention. In addition, the invention contemplates processes to prepare the compounds and uses of the compounds. The compounds of the invention may therefore be used in treating conditions mediated by the Wnt signalling pathway, for example, in treating cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, and leukemia; or enhancing the effectiveness of an anti-cancer treatment.

RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 15/514,061, filed Mar. 24, 2017; which is a § 371national stage application based on Patent Cooperation TreatyApplication serial number PCT/GB2015/052943, filed Oct. 8, 2015; whichclaims the benefit of priority to GB 1417832.1, filed Oct. 8, 2014; andGB 1512279.9, filed Jul. 14, 2015.

COMPOUNDS

This invention relates to compounds. More specifically, the inventionrelates to compounds useful as inhibitors of the Wnt signalling pathway.Specifically, inhibitors of Porcupine (Porcn) are contemplated by theinvention. In addition the invention contemplates processes to preparethe compounds and uses of the compounds.

The compounds of the invention may therefore be used in treatingconditions mediated by the Wnt signalling pathway, for example secretedWnt ligand mediated diseases which may be treated by inhibition ofporcupine; treating cancer, sarcoma, melanoma, skin cancer,haematological tumors, lymphoma, carcinoma, and leukemia; or enhancingthe effectiveness of an anti-cancer treatment.

BACKGROUND

The Wnt genes encode a large and highly conserved family of secretedgrowth factors. During normal development, transcription of Wnt familygenes is tightly regulated both temporally and spatially. To date, 19Wnt proteins have been discovered in humans. All of the Wnt proteins are38- to 43-kDa cysteine-rich glycoproteins. Wnts have a range of rolesduring development, governing cell fate, migration, proliferation anddeath. These include body axis formation in zebrafish and xenopus, wingand eye development in drosophila and brain development in mice (Parr,et al. (1994) Curr. Opinion Genetics & Devel. 4:523-528, McMahon A P,Bradley A (1990) Cell 62: 1073-1085). In adults the role of Wnts isthought to be linked to maintaining tissue homeostasis with aberrantsignalling implicated in a variety of cancers.

Wnt-mediated signalling occurs through binding of Wnt ligand to frizzled(Fzd) proteins, seven-transmembrane receptors. These receptors containan N-terminal cysteine rich domain (CRD) which serves as the Wnt bindingdomain. Binding is stabilised by low-density-lipoproteinreceptor-related proteins 5 and 6 (Lrp5 and Lrp6) (He, et al. (2004) DevApril; 131(8):1663-77). Fizzled ligation by Wnt is known to activate atleast three different signalling pathways including the “canonical”β-catenin pathway, “non-canonical” planar cell polarity (PCP) andcalcium pathways. Wnt signalling is further regulated by alternativereceptors, including Ror2, secreted antagonists, such as WIF-1 (Hsieh,et al. (1999) Nature April 1; 398(6726):431-6) and alternative Wntreceptors, such as Dickkopf (DKK) (Niehrs C (2006) Oncogene December 4;25(57):7469-81).

When inactive, β-Catenin is rapidly turned over by a conglomeration ofseveral proteins known as the “destruction complex”. The complexconsists of Axin, adenomatous polyposis coli (APC), casein kinase(CK)-1a and glycogen synthasekinase (GSK)-3β (Hamada, et al. (1999)Science 12; 283(5408):1739-42). In this state, β-catenin isphosphorylated on serine-threonine on the amino terminus leading toubiquitination (Behrens, et al. (1998) Science 280: 596-599). In thecanonical pathway of Wnt activation, Wnt-ligated Fzd binds to andactivates cytoplasmic Dishevelled (Dvl) (Chen, et al. (2003) Science301:1391-94). Wnt-ligated Lrp5 and Lrp6 directly bind to cytoplasmicAxin, inhibiting its function as a destruction complex stabiliser (Zeng,et al. (2008) Dev. 135, 367-375). These associations lead to adestabilisation of the destruction complex and cytosolic accumulation ofβ-catenin. Stabilisation and accumulation of β-catenin leads to nucleartranslocation where it complexes with T cell factor/lymphoid enhancerfactor (TCF/LEF) high mobility group transcription factors and promotestranscription of target genes such as Cyclin D1, p21 and cMyc.

Oncogenic mutations in the β-catenin gene CTNNb1 exclusively affectspecific serine and threonine and surrounding residues vital fortargeted degradation by APC (Hart, et al. (1999) Curr. Biol. 9:207-210).This interaction is especially apparent in colorectal cancer, where themajority of tumours present with APC mutations and an increasedproportion of the remainder express CTNNb1 mutations (Iwao, et al.(1998) Cancer Res Mar. 1, 1998 58; 1021).

Many recent studies have investigated compounds targeting β-catenin orother downstream Wnt pathway proteins. Recent research suggests thatmodulating Wnt-Wnt receptor interaction at the cell surface is effectivein reducing cell oncogenicity. This has been shown in systems withtumourgenicity driven by Wnt ligand overexpression (Liu, et al. (2013)PNAS 10; 110(50):20224-9) and where Wnt expression is driven bydownstream pathway activation (Vincan et al., Differentiation 2005; 73:142-153). Vincan et al transfected non-functional Frd7 receptor into aSK-CO-1 cell line with a homozygous APC mutation driving Wnt pathwayactivation. These cells demonstrated modulated morphology and reducedtumour-forming efficiency compared to parental cells in a xenograftmodel. This data suggests that modulating Wnt ligand-mediated signallingmay have a beneficial effect even in malignancies with downstream Wntpathway mutations.

The described invention is proposed to inhibit Wnt-mediated signalling.This includes paracrine signalling in the tissues surrounding tumoursand autocrine and paracrine signalling in cancer cells.

Wnt proteins undergo post-translational modification, shown in severalmutation experiments to be vital for effective protein trafficking andsecretion (Tang, et al. (2012) Dev. Biol 364, 32-41, Takada, R. et al(2006) Dev. Cell 11, 791-801). Palmitoylation of Wnt proteins occurs atseveral conserved amino acids (C77, S209) and is performed by porcupine,an O-acetyltransferase, in the endoplasmic reticulum. Mutations inporcupine have been shown to be the cause of developmental disorders,including focal dermal hypoplasia, through impaired Wnt pathwaysignalling (Grzeschik, et al. (2007) Nat. Genet, 39 pp. 833-835). Thedependence of Wnt ligand signalling on porcupine and the body ofevidence linking Wnt pathway signalling to cancer has led to porcupinebeing identified as a potential anti-cancer target.

US 2014/0038922 discloses compounds that inhibit the Wnt signallingpathway and the use of these compounds in the treatment of Wntsignalling-related diseases. Similarly, WO 2012/003189 and WO2010/101849 disclose compounds and methods for modulating Wnt signallingpathway.

An aim of the present invention is to provide alternative or improvedWnt signalling modulators. For example, an aim of the present inventionis to provide alternative or improved Wnt signalling inhibitors,optionally inhibitors of porcupine.

Furthermore, it is an aim of certain embodiments of this invention toprovide new compounds for use in: Wnt mediated diseases, such assecreted Wnt ligand mediated diseases which may be treated by inhibitionof porcupine; treating cancer, sarcoma, melanoma, skin cancer,haematological tumors, lymphoma, carcinoma, and leukemia; or enhancingthe effectiveness of an anti-cancer treatment.

It is an aim of certain embodiments of this invention to provide newcancer treatments. In particular, it is an aim of certain embodiments ofthis invention to provide compounds which have comparable activity toexisting treatments, ideally they should have better activity. Certainembodiments of the invention also aim to provide improved solubilitycompared to prior art compounds and existing therapies. It isparticularly attractive for certain compounds of the invention toprovide better activity and better solubility over known compounds.

It is an aim of certain embodiments of this invention to providecompounds which exhibit reduced cytotoxicity relative to prior artcompounds and existing therapies.

Another aim of certain embodiments of this invention is to providecompounds having a convenient pharmacokinetic profile and a suitableduration of action following dosing. A further aim of certainembodiments of this invention is to provide compounds in which themetabolised fragment or fragments of the drug after absorption are GRAS(Generally Regarded As Safe).

Certain embodiments of the present invention satisfy some or all of theabove aims.

BRIEF SUMMARY OF THE DISCLOSURE

In accordance with the present invention there is provided a compound offormula (I):

whereinhet¹ represents a 8 or 9 membered bicyclic heterocyclic ring systemcomprising a 5 membered ring and 1, 2, 3 or 4 heteroatoms selected fromN, O or S, wherein the 8 or 9 membered bicyclic heterocyclic ring systemis unsubstituted or substituted, and when substituted the ring system issubstituted with 1, 2, or 3 groups independently selected at eachoccurrence from: halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —OR^(A2),—NR^(A2)R^(B2), —CN, —SO₂R^(A2), and C₃₋₆ cycloalkyl;het² is a 5 or 6 membered heterocyclic ring which may be unsubstitutedor substituted, and when substituted the ring is substituted with 1, 2or 3 groups independently selected at each occurrence from: halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, —OR^(A1), —NR^(A1)R^(B1), —CN, —NO₂,—NR^(A1)C(O)R^(B1), —C(O)NR^(A1)R^(B1), —NR^(A1) SO₂R^(B1),—SO₂NR^(A1)R^(B1), —SO₂R^(A1), —C(O)R^(A1), —C(O)OR^(A1) and C₃₋₆cycloalkyl;het³ is a 6 membered heterocyclic ring which may be unsubstituted orsubstituted, and when substituted the ring is substituted with 1, 2 or 3groups independently selected at each occurrence from: halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, —OR^(A1), —NR^(A1)R^(B1), —CN, —NO₂, —NR^(A1)C(O)R^(B1),—C(O)NR^(A1)R^(B1), —NR^(A1) SO₂R^(B1), —SO₂NR^(A1)R^(B1), —SO₂R^(A1),—C(O)R^(A1), —C(O)OR^(A1) and C₃₋₆ cycloalkyl;R¹ and R² are independently selected at each occurrence from: H, halo,C₁₋₄ alkyl, C₁₋₄ haloalkyl, —OR^(A3), —NR^(A3)R^(B3) and C₃₋₆cycloalkyl;R³ is selected from: H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₆ cycloalkyl;R⁴ is independently selected at each occurrence from: halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, —CN, —OR^(A4), —NR^(A4)R^(B4), —SO₂R^(A4), C₃₋₆cycloalkyl and C₃₋₆ halocycloalkyl;m is selected from, 1, 2 or 3;n is selected from 0, 1 or 2; andR^(A1), R^(B1), R^(A2), R^(B2), R^(A3), R^(B3), R^(A4) and R^(B4) are ateach occurrence independently selected from: H, C₁₋₄ alkyl, C₁₋₄haloalkyl.

The invention also provides pharmaceutically acceptable salts ofcompounds of the invention. Accordingly, there is provided compounds offormula (I) and pharmaceutically acceptable salts thereof.

In an embodiment the compound according to formula (I) is a compoundaccording to formulae (IIa) or (IIb):

Het² may be represented by an aromatic, saturated or unsaturated 5 or 6membered heterocyclic ring which is unsubstituted or substituted.

Het² may be represented by a ring selected from unsubstituted orsubstituted: pyrazole, imidazole, pyridine, pyrazine, pyrimidine,pyridazine, pyran, tetrahydropyran, dihydropyran, piperidine,piperazine, morpholine, thiomorpholine, oxazine, dioxine, dioxane,thiazine, oxathiane and dithiane.

Preferably, het² may be represented by unsubstituted or substituted:pyrazole, imidazole, pyridine, tetrahydropyran, dihydropyran,piperidine, piperazine and morpholine.

Optionally, het² is represented by an unsubstituted or substitutedpyridine.

Het² may be unsubstituted or substituted with 1, 2, or 3 groups selectedfrom: halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —OR^(A1), —NR^(A1)R^(B1), —CN,and C₃₋₆ cycloalkyl. Preferably, het² may be unsubstituted orsubstituted with 1, 2, or 3 groups selected from: halo, C₁₋₄ alkyl,—OR^(A1), and C₁₋₄ haloalkyl, wherein R^(A1) is H, methyl, ortrifluoromethyl.

In a preferred embodiment het² is unsubstituted or substituted with 1 or2 groups selected from: fluoro, chloro, methyl, ethyl, trifluoromethyl,trifluoroethyl, —CN and —OCF₃. In a particularly preferred embodimenthet² is unsubstituted or substituted with 1 or 2 groups selected frommethyl and trifluoromethyl.

Preferably, het² is unsubstituted or substituted with 1 or 2 groups.More preferably, het² is unsubstituted or substituted with 1 group.

Het² may be unsubstituted pyridine, unsubstituted pyrazole,unsubstituted tetrahydropyran, unsubstituted dihydropyran, unsubstitutedpiperidine, unsubstituted piperazine and unsubstituted morpholine,methylpyridine, dimethylpyridine, ethylpyridine, iso-propylpyridine,tert-butylpyridine, trifluoromethylpyridine, methoxypyridine,ethyoxypyridine, aminopyridine, N-methyl-aminopyridine,N,N-dimethyl-aminopyridine, nitropyridine, cyanopyridine,methyltetrahydropyran, dimethyltetrahydropyran, ethyltetrahydropyran,iso-propyltetrahydropyran, tert-butyltetrahydropyran,trifluoromethyltetrahydropyran, methoxytetrahydropyran,ethyoxytetrahydropyran, aminotetrahydropyran,N-methyl-aminotetrahydropyran, N,N-dimethyl-aminotetrahydropyran,nitrotetrahydropyran, cyanotetrahydropyran, methyldihydropyran,dimethyldihydropyran, ethyldihydropyran, iso-propyldihydropyran,tert-butyldihydropyran, trifluoromethyldihydropyran,methoxydihydropyran, ethyoxydihydropyran, aminodihydropyran,N-methyl-aminodihydropyran, N,N-dimethyl-aminodihydropyran,nitrodihydropyran, cyanodihydropyran, methylpiperidine,dimethylpiperidine, ethylpiperidine, iso-propylpiperidine,tert-butylpiperidine, trifluoromethylpiperidine, methoxypiperidine,ethyoxypiperidine, aminopiperidine, N-methyl-aminopiperidine,N,N-dimethyl-aminopiperidine, nitropiperidine, cyanopiperidine,methylpiperazine, dimethylpiperazine, ethylpiperazine,iso-propylpiperazine, tert-butylpiperazine, trifluoromethylpiperazine,methoxypiperazine, ethyoxypiperazine, aminopiperazine,N-methyl-aminopiperazine, N,N-dimethyl-aminopiperazine, nitropiperazine,cyanopiperazine, methylmorpholine, dimethylmorpholine, ethylmorpholine,iso-propylmorpholine, tert-butylmorpholine, trifluoromethylmorpholine,methoxymorpholine, ethyoxymorpholine, aminomorpholine,N-methyl-aminomorpholine, N,N-dimethyl-aminomorpholine, nitromorpholine,cyanomorpholine, methylpyrazole, dimethylpyrazole, ethylpyrazole,iso-propylpyrazole, tert-butylpyrazole, trifluoromethylpyrazole,methoxypyrazole, ethyoxypyrazole, aminopyrazole, N-methyl-aminopyrazole,N,N-dimethyl-aminopyrazole, nitropyrazole, or cyanopyrazole.

Het³ may be represented by an aromatic, saturated or unsaturated 6membered heterocyclic ring which is unsubstituted or substituted andcomprises at least one nitrogen atom. Preferably the ring is aromatic orsaturated. Optionally, het³ is not pyridine.

Het³ may be represented by an aromatic, saturated or unsaturated 6membered heterocyclic ring which is unsubstituted or substituted andcomprises 2 heteroatoms, preferably the ring is aromatic or saturated.In a preferred embodiment het³ is represented by an aromatic, saturatedor unsaturated 6 membered heterocyclic ring which is unsubstituted orsubstituted and comprises 2 nitrogen atoms, preferably the ring isaromatic or saturated.

Het³ may be represented by a ring selected from unsubstituted orsubstituted: pyrimidine, pyrazine, pyridazine, piperazine, dioxine,dioxane, morpholine and thiomorpholine.

Preferably, het³ may be represented by a ring selected from pyrimidine,pyrazine, pyridazine or piperazine.

Preferably, het³ may be represented by a ring selected from pyrimidine,pyrazine or pyridazine.

Optionally, het³ is represented by a ring selected from unsubstituted orsubstituted: pyrimidine and pyrazine. Preferably, het³ is represented bya ring selected from unsubstituted or substituted pyrazine.

Het³ may be unsubstituted or substituted with 1, 2, or 3 groups selectedfrom: halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —OR^(A1), —NR^(A1)R^(B1), —CN,—C(O)R^(A1), —C(O)OR^(A1) and C₃₋₆ cycloalkyl. Preferably, het³ may beunsubstituted or substituted with 1, 2, or 3 groups selected from: halo,C₁₋₄ alkyl, C₁₋₄ haloalkyl, —OR^(A1), —C(O)R^(A1) and —C(O)OR^(A1),wherein R^(A1) is H, methyl, tert-butyl or trifluoromethyl.

In a particular preferred embodiment het³ is unsubstituted orsubstituted with 1 or 2 groups selected from: fluoro, chloro, methyl,ethyl, trifluoromethyl, trifluoroethyl, —OCF₃, —C(O)Me, —C(O)OMe,—C(O)Et and —C(O)O^(t)Bu.

Preferably, het³ is unsubstituted or substituted with 1 or 2 groups.More preferably, het³ is unsubstituted or substituted with 1 group.

In an embodiment het² is represented by an aromatic, saturated orunsaturated 6 membered heterocyclic ring which is unsubstituted orsubstituted, and het³ is represented by an aromatic, saturated orunsaturated 6 membered heterocyclic ring which is unsubstituted orsubstituted and comprises 2 heteroatoms.

In an embodiment het² is represented by a ring selected fromunsubstituted or substituted: pyridine, pyrazole, imidazole, pyrazine,pyrimidine, pyridazine, pyran, tetrahydropyran, dihydropyran,piperidine, piperazine, morpholine, thiomorpholine, oxazine, dioxine,dioxane, thiazine, oxathiane and dithiane; and het³ is represented by aring selected from unsubstituted or substituted: pyrimidine, pyrazine,pyridazine, piperazine, dioxine, dioxane, morpholine and thiomorpholine.

Preferably, het² is represented by a ring selected from unsubstituted orsubstituted: pyridine, pyrazole, imidazole, tetrahydropyran,dihydropyran, piperidine, piperazine and morpholine; and het³ isrepresented by a ring selected from unsubstituted or substituted:pyrimidine, pyrazine, pyridazine and piperazine.

Het¹ represents a substituted or unsubstituted 8 or 9 membered bicyclicheteroaryl group comprising a 5 membered ring and comprising 1, 2, 3 or4 heteroatoms selected from N, O or S. Het¹ represents a substituted orunsubstituted 9 membered bicyclic heteroaryl group comprising a 5membered ring and a 6 membered ring, wherein the 5 membered ringcomprises 1 or 2 N atoms and the 6-membered ring comprises 1 or 2 Natoms.

Het¹ may represent a group selected from unsubstituted or substituted:indolizine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, benzothiazole, benzoxazole,benzisothiazole, benzisoxazole, imidazopyridine, imidazopyrimidine,indazole, azaindazole, purine, azaindole, and azaisoindole.

Het¹ may represent a group selected from unsubstituted or substituted:indolizine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, benzothiazole, benzoxazole,benzisothiazole, benzisoxazole, imidazopyridine, imidazopyrimidine,indazole, azaindazole, purine, pyrrolopyrimidine, pyrazolopyrimidine,pyrazolopyridine, azaindole, and azaisoindole.

Het¹ represents a group selected from unsubstituted or substituted:indolizine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, benzothiazole, benzoxazole,benzisothiazole, benzisoxazole, purine, pyrrolopyrimidine,pyrazolopyrimidine, pyrazolopyridine, azaindole, and azaisoindole.

Het¹ may represent a group selected from unsubstituted or substituted:imidazopyridine, imidazopyrimidine, azaindazole, purine,pyrrolopyrimidine, pyrazolopyrimidine, pyrazolopyridine, azaindole, andazaisoindole.

Optionally, het¹ may represent a group selected from unsubstituted orsubstituted: indolizine

Preferably het¹ represents an unsubstituted or substitutedpyrrolopyrimidine or azaindole. Preferably het¹ represents anunsubstituted or substituted azaindole.

When het¹ represents azaindole, the azaindole may be 5-azaindole,6-azaindole or 7-azaindole, preferably 7-azaindole.

Het¹ may be unsubstituted or substituted with 1, 2, or 3 groups(preferably 1 or 2) selected from: halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,—OR^(A2), —NR^(A2)R^(B2) and —CN. Het¹ may be unsubstituted orsubstituted with 1 or 2 groups selected from: chloro, fluoro, methyl,ethyl, trifluoromethyl, trifluoroethyl, —OCF₃, —OH, —OMe, —OEt, —NH₂,—NHMe, —NMe₂ and —CN. Preferably, Het¹ may be unsubstituted orsubstituted with 1 or 2 methyl groups.

In an embodiment het¹ represents a group selected from unsubstituted orsubstituted:indolizine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, benzothiazole, benzoxazole,benzisothiazole, benzisoxazole, imidazopyridine, imidazopyrimidine,indazole, azaindazole, purine, azaindole, and azaisoindole; het² isrepresented by an aromatic, saturated or unsaturated 6 memberedheterocyclic ring which is unsubstituted or substituted; and het³ isrepresented by an aromatic, saturated or unsaturated 6 memberedheterocyclic ring which is unsubstituted or substituted and comprises 2heteroatoms.

In an embodiment het¹ represents a group selected from unsubstituted orsubstituted:indolizine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, benzothiazole, benzoxazole,benzisothiazole, benzisoxazole, imidazopyridine, imidazopyrimidine,indazole, azaindazole, purine, pyrrolopyrimidine, pyrazolopyrimidine,azaindole, and azaisoindole; het² is represented by an aromatic,saturated or unsaturated 6 membered heterocyclic ring which isunsubstituted or substituted; and het³ is represented by an aromatic,saturated or unsaturated 6 membered heterocyclic ring which isunsubstituted or substituted and comprises 2 heteroatoms.

In an embodiment het¹ represents a group selected from unsubstituted orsubstituted: indolizine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, benzothiazole, benzoxazole,benzisothiazole, benzisoxazole, imidazopyridine, imidazopyrimidine,indazole, azaindazole, purine, azaindole, and azaisoindole; het² isrepresented by a ring selected from unsubstituted or substituted:pyrazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, pyran,tetrahydropyran, dihydropyran, piperidine, piperazine, morpholine,thiomorpholine, oxazine, dioxine, dioxane, thiazine, oxathiane anddithiane; het² is represented by unsubstituted or substituted pyridine;and het³ is represented by a ring selected from unsubstituted orsubstituted: pyrimidine, pyrazine, pyridazine, piperazine, dioxine,dioxane, morpholine and thiomorpholine.

In an embodiment het¹ represents a group selected from unsubstituted orsubstituted: indolizine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, benzothiazole, benzoxazole,benzisothiazole, benzisoxazole, imidazopyridine, imidazopyrimidine,indazole, azaindazole, purine, pyrrolopyrimidine, pyrazolopyrimidine,azaindole, and azaisoindole; het² is represented by a ring selected fromunsubstituted or substituted: pyrazole, imidazole, pyridine, pyrazine,pyrimidine, pyridazine, pyran, tetrahydropyran, dihydropyran,piperidine, piperazine, morpholine, thiomorpholine, oxazine, dioxine,dioxane, thiazine, oxathiane and dithiane; het² is represented byunsubstituted or substituted pyridine; and het³ is represented by a ringselected from unsubstituted or substituted: pyrimidine, pyrazine,pyridazine, piperazine, dioxine, dioxane, morpholine and thiomorpholine.

Optionally, het¹ represents a group selected from unsubstituted orsubstituted: indolizine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, benzothiazole, benzoxazole,benzisothiazole, benzisoxazole, imidazopyridine, imidazopyrimidine,indazole, azaindazole, purine, azaindole, and azaisoindole; het² isrepresented by a ring selected from unsubstituted or substituted:pyrazole, imidazole, pyridine, tetrahydropyran, dihydropyran,piperidine, piperazine and morpholine; and het³ is represented by a ringselected from unsubstituted or substituted: pyrimidine, pyrazine,pyridazine and piperazine.

Optionally, het¹ represents a group selected from unsubstituted orsubstituted: indolizine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, benzothiazole, benzoxazole,benzisothiazole, benzisoxazole, imidazopyridine, imidazopyrimidine,indazole, azaindazole, purine, pyrrolopyrimidine, pyrazolopyrimidine,azaindole, and azaisoindole; het² is represented by a ring selected fromunsubstituted or substituted: pyrazole, imidazole, pyridine,tetrahydropyran, dihydropyran, piperidine, piperazine and morpholine;and het³ is represented by a ring selected from unsubstituted orsubstituted: pyrimidine, pyrazine, pyridazine and piperazine.

In an embodiment m is 1 or 2. In a preferred embodiment m is 1.

In an embodiment the compound according to formula (I) is a compoundaccording to formula (III):

In an embodiment the compound according to formula (I) is a compoundaccording to formulae (IIIa) or (IIIb):

In an embodiment the compound according to formula (I) is a compoundaccording to formulae (IVa) or (IVb):

In an embodiment the compound according to formula (I) is a compoundaccording to formulae (Va) or (Vb):

In an embodiment het¹ represents an unsubstituted or substitutedazaindole; het² is represented by an aromatic, saturated or unsaturated6 membered heterocyclic ring which is unsubstituted or substituted, andhet³ is represented by an aromatic, saturated or unsaturated 6 memberedheterocyclic ring which is unsubstituted or substituted and comprises 2heteroatoms.

In an embodiment het¹ represents an unsubstituted or substitutedazaindole; het² is represented by a ring selected from unsubstituted orsubstituted: pyrazole, imidazole, pyridine, pyrazine, pyrimidine,pyridazine, pyran, tetrahydropyran, dihydropyran, piperidine,piperazine, morpholine, thiomorpholine, oxazine, dioxine, dioxane,thiazine, oxathiane and dithiane; and het³ is represented by a ringselected from unsubstituted or substituted: pyrimidine, pyrazine,pyridazine, piperazine, dioxine, dioxane, morpholine and thiomorpholine.

Optionally, het¹ represents an unsubstituted or substituted azaindole;het² is represented by a ring selected from unsubstituted orsubstituted: pyrazole, imidazole, pyridine, tetrahydropyran,dihydropyran, piperidine, piperazine and morpholine; and het³ isrepresented by a ring selected from unsubstituted or substituted:pyrimidine, pyrazine, pyridazine and piperazine.

In a preferred embodiment het¹ represents an unsubstituted orsubstituted: azaindole; het² is represented by an unsubstituted orsubstituted pyridine; and het³ is represented by a ring selected fromunsubstituted or substituted: pyrimidine, and pyrazine.

In an embodiment the compound according to formula (I) is a compoundaccording to formula (VI):

In an embodiment the compound according to formula (I) is a compoundaccording to formulae (VIa) or (VIb):

R¹ and R² may be independently selected at each occurrence from: H,halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —OR^(A3) and —NR^(A3)R^(B3). R¹ and R²may be independently selected at each occurrence from: H, chloro,fluoro, methyl, ethyl, trifluoromethyl, trifluoroethyl, —OCF₃, —OH,—OMe, —OEt, —NH₂, —NHMe, and —NMe₂. Preferably, R¹ and R² are H.

In an embodiment m is 1 and R¹ and R² are H. In an alternativeembodiment m is 2 and R¹ and R² are H. In an alternative embodiment m is1 and R¹ is Me R² are H.

R³ is optionally H or methyl.

R⁴ is optionally selected at each occurrence from: halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, —CN, —OR^(A4) and —NR^(A4)R^(B4). R⁴ may beindependently selected at each occurrence from: H, chloro, fluoro,methyl, ethyl, trifluoromethyl, trifluoroethyl, —OCF₃, —OH, —OMe, —OEt,—NH₂, —NHMe, and —NMe₂.

R^(A1), R^(B1), R^(A2), R^(B2), R^(A3), R^(B3), R^(A4) and R^(B4) are ateach occurrence independently selected from: H, methyl, ethyl and —OCF₃.

In a preferred embodiment the compound of formula (I) is a compoundaccording to formulae (IIa), (IIIa), (IVa), (Va) or (VIa).

In a preferred embodiment n is 0.

The compound according to the invention may be selected from a groupconsisting of:

The compound according to the invention may also be selected from agroup consisting of:

The compound according to the invention may also be selected from agroup consisting of:

In accordance with another aspect, the present invention provides acompound of the present invention for use as a medicament.

In accordance with another aspect, the present invention provides apharmaceutical formulation comprising a compound of the presentinvention and a pharmaceutically acceptable excipient.

In an embodiment the pharmaceutical composition may be a combinationproduct comprising an additional pharmaceutically active agent. Theadditional pharmaceutically active agent may be an anti-tumor agentdescribed below.

In accordance with another aspect, there is provided a compound of thepresent invention for use in the modulation of Wnt signalling.Optionally, the Wnt signalling is modulated by the inhibition ofporcupine (Porcn). Modulation of Wnt signalling may include inhibitionof paracrine signalling in the tissues surrounding tumours and autocrineand paracrine signalling in cancer cells

In accordance with another aspect, there is provided a compound of thepresent invention for use in the treatment of a condition which can bemodulated by inhibition of Porcn using a compound of the presentinvention. A compound of formula (I) may be for use in the treatment ofa condition treatable by the inhibition of Porcn.

Porcn inhibition is relevant for the treatment of many differentdiseases associated with increased Wnt signalling. In embodiments thecondition treatable by the modulation of Wnt signalling or theinhibition of Porcn may be selected from: cancer, sarcoma, melanoma,skin cancer, haematological tumors, lymphoma, carcinoma, and leukemia.Specific cancers, sarcomas, melanomas, skin cancers, haematologicaltumors, lymphoma, carcinoma and leukemia treatable by the modulation ofWnt signalling or the inhibition of Porcn may be selected from:esophageal squamous cell carcinoma, gastric cancer, glioblastomas,astrocytomas; retinoblastoma, osteosarcoma, chondosarcoma, Ewing'ssarcoma, rabdomysarcoma, Wilm's tumor, basal cell carcinoma, non-smallcell lung cancer, brain tumour, hormone refractory prostate cancer,prostate cancer, metastatic breast cancer, breast cancer, metastaticpancreatic cancer, pancreatic cancer, colorectal cancer, cervicalcancer, head and neck squamous cell carcinoma and cancer of the head andneck.

Porcn inhibition is also relevant for the treatment of a conditiontreatable by the inhibition of Wnt ligand secretion selected from: skinfibrosis, idiopathic pulmonary fibrosis, renal interstitial fibrosis,liver fibrosis, proteinuria, kidney graft rejection, osteoarthritis,Parkinsons's disease, cystoid macular edema, uveitis associated cystoidmacular edema, retinopathy, diabetic retinopathy and retinopathy ofprematurity.

The invention contemplates methods of treating the above mentionedconditions and contemplates compounds of the invention for use in amethod of treatment of the above mentioned conditions.

In an aspect of the invention, a compound of the invention may be foruse in the treatment of a condition selected from: cancer, sarcoma,melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, andleukemia. Specific cancer, sarcoma, melanoma, skin cancer,haematological tumors, lymphoma, carcinoma, and leukemia that may betreated by the compound of the invention may be selected from:esophageal squamous cell carcinoma, gastric cancer, glioblastomas,astrocytomas; retinoblastoma, osteosarcoma, chondosarcoma, Ewing'ssarcoma, rabdomysarcoma, Wilm's tumor, basal cell carcinoma, non-smallcell lung cancer, brain tumour, hormone refractory prostate cancer,prostate cancer, metastatic breast cancer, breast cancer, metastaticpancreatic cancer, pancreatic cancer, colorectal cancer, cervicalcancer, head and neck squamous cell carcinoma and cancer of the head andneck.

The compound of the invention also may be for use in the treatment of acondition selected from: skin fibrosis, idiopathic pulmonary fibrosis,renal interstitial fibrosis, liver fibrosis, proteinuria, kidney graftrejection, osteoarthritis, Parkinsons's disease, cystoid macular edema,uveitis associated cystoid macular edema, retinopathy, diabeticretinopathy and retinopathy of prematurity.

In an aspect of the invention there is provided a method of treatment ofa condition which is modulated by Wnt signalling, wherein the methodcomprises administering a therapeutic amount of a compound of theinvention, to a patient in need thereof. In an embodiment of theinvention there is provided a method of treatment of a condition whichis modulated by Porcn.

The method of treatment may be a method of treating a conditiontreatable by the modulation of Wnt signalling or Porcn. These conditionsare described above in relation to conditions treatable by theinhibition of Porcn.

In an aspect of the invention there is provided a method of treatment ofa condition selected from: cancer, sarcoma, melanoma, skin cancer,haematological tumors, lymphoma, carcinoma, and leukemia, wherein themethod comprises administering a therapeutic amount of a compound of theinvention, to a patient in need thereof. Specific cancer, sarcoma,melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, andleukemia that may be treated by the method of treatment may be selectedfrom: esophageal squamous cell carcinoma, gastric cancer, glioblastomas,astrocytomas; retinoblastoma, osteosarcoma, chondosarcoma, Ewing'ssarcoma, rabdomysarcoma, Wilm's tumor, basal cell carcinoma, non-smallcell lung cancer, brain tumour, hormone refractory prostate cancer,prostate cancer, metastatic breast cancer, breast cancer, metastaticpancreatic cancer, pancreatic cancer, colorectal cancer, cervicalcancer, head and neck squamous cell carcinoma and cancer of the head andneck.

The method of treatment also may be the treatment of a conditionselected from: skin fibrosis, idiopathic pulmonary fibrosis, renalinterstitial fibrosis, liver fibrosis, proteinuria, kidney graftrejection, osteoarthritis, Parkinson's disease, cystoid macular edema,uveitis associated cystoid macular edema, retinopathy, diabeticretinopathy and retinopathy of prematurity.

In an aspect of the invention there is provided a use of a compound ofthe invention in the manufacture of a medicament for the treatment of acondition which is modulated by Porcn. The condition may be any of theconditions mentioned above.

Aberrant Wnt signalling may be associated with a condition selectedfrom: non small cell lung cancer (NSCLC); chronic lymphocytic leukemia(CLL); gastric cancer; head and neck squamous cell carcinoma (HNSCC);colorectal cancer; ovarian cancer; basal cell carcinoma (BCC); breastcancer; bladder cancer; mesothelioma colorectal; prostate cancer;non-small cell lung cancer; lung cancer; osteosarcoma; Frzoverexpression; has been associated with cancers such as prostate;colorectal; ovarian cancer; gastric; overexpression of Wnt signalingpathway components such as disheveled; prostate cancer; breast cancer;mesothelioma; cervical; Frat-1 overexpression; pancreatic cancer;esophageal cancer; cervical cancer; breast cancer; and gastric cancer;Axin loss of function (LOF); hepatocellular cancer; medulloblastoma;gastric cancer; colorectal cancer; intestinal carcinoid; ovarian cancer;pulmonary adenocarcinoma; endometrial cancer; hepatocellular;hepatoblastoma; medulloblastoma; pancreatic cancer; thyroid cancer;prostate cancer; melanoma; pilomatricoma; Wilms' tumor;pancreatoblastomas; liposarcomas; juvenile nasopharyngeal angiofibromas;desmoid; synovial sarcoma; melanoma; leukemia; multiple myeloma; braintumors, such as gliomas, astrocytomas, meningiomas, schwannomas,pituitary tumors, primitive neuroectodermal tumors (PNET),medulloblastomas, craniopharyngioma, pineal region tumors, and noncancerous neurofibromatoses;

Inhibition of Wnt signaling with the Wnt antagonists of the presentinvention may be therapeutic in the treatment of disorders resultingfrom dysfunctional hematopoieses, such as leukemias and various bloodrelated cancers, such as acute, chronic, lymphoid and myelogenousleukemias, myelodysplastic syndrome and myeloproliferative disorders.These include myeloma, lymphoma (e.g., Hodgkin's and non-Hodgkin's)chronic and nonprogressive anemia, progressive and symptomatic bloodcell deficiencies, polycythemia vera, essential or primarythrombocythemia, idiopathic myelofibrosis, chronic myelomonocyticleukemia (CMML), mantle cell lymphoma, cutaneous T-cell lymphoma, andWaldenstrom macro globinemia.

Other disorders associated with aberrant Wnt signaling, include but arenot limited to osteoporosis, osteoarthritis, polycystic kidney disease,diabetes, schizophrenia, vascular disease, cardiac disease,non-oncogenic proliferative diseases, and neurodegenerative diseasessuch as Alzheimer's disease.

Aberrant Wnt signalling may be associated with a cancer selected from:brain; lung; colon; epidermoid; squamous cell; bladder; gastric;pancreatic; breast; head and neck; renal; kidney; liver; ovarian;prostate; uterine; oesophageal; testicular; gynaecological; thyroid;melanoma; acute myeloid leukemia; chronic myelogenous leukemia; MCLKaposi's sarcoma;

Aberrant Wnt signalling may be associated with an inflammatory diseaseselected from: multiple sclerosis; rheumatoid arthritis; systemic lupus;inflammatory bowel disease; osteoarthritis; Alzheimer's;

DETAILED DESCRIPTION

Given below are definitions of terms used in this application. Any termnot defined herein takes the normal meaning as the skilled person wouldunderstand the term.

The term “halo” refers to one of the halogens, group 17 of the periodictable. In particular the term refers to fluorine, chlorine, bromine andiodine. Preferably, the term refers to fluorine or chlorine.

The term “C₁₋₄ alkyl” refers to a linear or branched hydrocarbon chaincontaining 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl andn-hexyl. Alkylene groups may likewise be linear or branched and may havetwo places of attachment to the remainder of the molecule. Furthermore,an alkylene group may, for example, correspond to one of those alkylgroups listed in this paragraph. The alkyl and alkylene groups may beunsubstituted or substituted by one or more substituents. Possiblesubstituents are described below. Substituents for the alkyl group maybe halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C₁₋₆alkoxy.

The term “C₁₋₄ alkoxy” refers to an alkyl group which is attached to amolecule via oxygen. This includes moieties where the alkyl part may belinear or branched and may contain 1, 2, 3, 4, 5 or 6 carbon atoms, forexample methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,tert-butyl, n-pentyl and n-hexyl. Therefore, the alkoxy group may bemethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy,tert-butoxy, n-pentoxy and n-henoxy. The alkyl part of the alkoxy groupmay be unsubstituted or substituted by one or more substituents.Possible substituents are described below. Substituents for the alkylgroup may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH,C₁₋₆ alkoxy.

The term “C₁₋₄ haloalkyl” refers to a hydrocarbon chain substituted withat least one halogen atom independently chosen at each occurrence, forexample fluorine, chlorine, bromine and iodine. The halogen atom may bepresent at any position on the hydrocarbon chain. For example, C₁₋₆haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl,chloroethyl e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl e.g.1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g.1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g.1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl,trichloropropyl, fluoropropyl, trifluoropropyl.

The term “C₂₋₆ alkenyl” refers to a branched or linear hydrocarbon chaincontaining at least one double bond and having 2, 3, 4, 5 or 6 carbonatoms. The double bond(s) may be present as the E or Z isomer. Thedouble bond may be at any possible position of the hydrocarbon chain.For example, the “C₂₋₆ alkenyl” may be ethenyl, propenyl, butenyl,butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

The term “C₂₋₆ alkynyl” refers to a branched or linear hydrocarbon chaincontaining at least one triple bond and having 2, 3, 4, 5 or 6 carbonatoms. The triple bond may be at any possible position of thehydrocarbon chain. For example, the “C₂₋₆ alkynyl” may be ethynyl,propynyl, butynyl, pentynyl and hexynyl.

The term “C₁₋₆ heteroalkyl” refers to a branched or linear hydrocarbonchain containing 1, 2, 3, 4, 5, or 6 carbon atoms and at least oneheteroatom selected from N, O and S positioned between any carbon in thechain or at an end of the chain. For example, the hydrocarbon chain maycontain one or two heteroatoms. The C₁₋₆ heteroalkyl may be bonded tothe rest of the molecule through a carbon or a heteroatom. For example,the “C₁₋₆ heteroalkyl” may be C₁-6 N-alkyl, C₁₋₆ N,N-alkyl, or C₁₋₆O-alkyl.

The term “carbocyclic” refers to a saturated or unsaturated carboncontaining ring system. A “carbocyclic” system may be monocyclic or afused polycyclic ring system, for example, bicyclic or tricyclic. A“carbocyclic” moiety may contain from 3 to 14 carbon atoms, for example,3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in apolycyclic system. “Carbocyclic” encompasses cycloalkyl moieties,cycloalkenyl moieties, aryl ring systems and fused ring systemsincluding an aromatic portion.

The term “heterocyclic” refers to a saturated or unsaturated ring systemcontaining at least one heteroatom selected from N, O or S. A“heterocyclic” system may contain 1, 2, 3 or 4 heteroatoms, for example1 or 2. A “heterocyclic” system may be monocyclic or a fused polycyclicring system, for example, bicyclic or tricyclic. A “heterocyclic” moietymay contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atomsin a monocyclic system and 7 to 14 carbon atoms in a polycyclic system.“Heterocyclic” encompasses heterocycloalkyl moieties, heterocycloalkenylmoieties and heteroaromatic moieties. For example, the heterocyclicgroup may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran,pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine,thiomorpholine, piperazine, and tetrahydropyran.

The term “C₃₋₆ cycloalkyl” refers to a saturated hydrocarbon ring systemcontaining 3, 4, 5, 6, 7 or 8 carbon atoms. For example, the “C₃₋₆cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

The term “C₃₋₆ cycloalkenyl” refers to an unsaturated hydrocarbon ringsystem containing 3, 4, 5, 6, 7 or 8 carbon atoms that is not aromatic.The ring may contain more than one double bond provided that the ringsystem is not aromatic. For example, the “C₃₋₆ cycloalkyl” may becyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene,cyclooctenyl and cycloatadienyl.

The term “C₃₋₆ heterocycloalkyl” refers to a saturated hydrocarbon ringsystem containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least oneheteroatom within the ring selected from N, O and S. For example theremay be 1, 2 or 3 heteroatoms, optionally 1 or 2. The “C₃₋₆heterocycloalkyl” may be bonded to the rest of the molecule through anycarbon atom or heteroatom. The “C₃₋₆ heterocycloalkyl” may have one ormore, e.g. one or two, bonds to the rest of the molecule: these bondsmay be through any of the atoms in the ring. For example, the “C₃₋₆heterocycloalkyl” may be oxirane, aziridine, azetidine, oxetane,tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine,morpholine, thiomorpholine, piperazine, and tetrahydropyran.

The term “C₃₋₆ heterocycloalkenyl” refers to an unsaturated hydrocarbonring system, that is not aromatic, containing 3, 4, 5, 6, 7 or 8 carbonatoms and at least one heteroatom within the ring selected from N, O andS. For example there may be 1, 2 or 3 heteroatoms, optionally 1 or 2.

The “C₃₋₆ heterocycloalkenyl” may be bonded to the rest of the moleculethrough any carbon atom or heteroatom. The “C₃₋₆ heterocycloalkenyl” mayhave one or more, e.g. one or two, bonds to the rest of the molecule:these bonds may be through any of the atoms in the ring. For example,the “C₃₋₆ heterocycloalkyl” may be tetrahydropyridine, dihydropyran,dihydrofuran, pyrroline.

The term “aromatic” when applied to a substituent as a whole means asingle ring or polycyclic ring system with 4n+2 electrons in aconjugated π system within the ring or ring system where all atomscontributing to the conjugated π system are in the same plane.

The term “aryl” refers to an aromatic hydrocarbon ring system. The ringsystem has 4n+2 electrons in a conjugated π system within a ring whereall atoms contributing to the conjugated π system are in the same plane.For example, the “aryl” may be phenyl and naphthyl. The aryl systemitself may be substituted with other groups.

The term “heteroaryl” refers to an aromatic hydrocarbon ring system withat least one heteroatom within a single ring or within a fused ringsystem, selected from O, N and S. The ring or ring system has 4n+2electrons in a conjugated π system where all atoms contributing to theconjugated π system are in the same plane. For example, the “heteroaryl”may be imidazole, thiene, furane, thianthrene, pyrrol, benzimidazole,pyrazole, pyrazine, pyridine, pyrimidine and indole.

The term “alkaryl” refers to an aryl group, as defined above, bonded toa C₁₋₄ alkyl, where the C₁₋₄ alkyl group provides attachment to theremainder of the molecule.

The term “alkheteroaryl” refers to a heteroaryl group, as defined above,bonded to a C₁₋₄ alkyl, where the alkyl group provides attachment to theremainder of the molecule.

The term “halogen” herein includes reference to F, Cl, Br and I. Halogenmay be Cl. Halogen may be F.

A bond terminating in a “

” represents that the bond is connected to another atom that is notshown in the structure. A bond terminating inside a cyclic structure andnot terminating at an atom of the ring structure represents that thebond may be connected to any of the atoms in the ring structure whereallowed by valency.

Where a moiety is substituted, it may be substituted at any point on themoiety where chemically possible and consistent with atomic valencyrequirements. The moiety may be substituted by one or more substituents,e.g. 1, 2, 3 or 4 substituents; optionally there are 1 or 2 substituentson a group. Where there are two or more substituents, the substituentsmay be the same or different. The substituent(s) may be selected from:OH, NHR, amidino, guanidino, hydroxyguanidino, formamidino,isothioureido, ureido, mercapto, C(O)H, acyl, acyloxy, carboxy, sulfo,sulfamoyl, carbamoyl, cyano, azo, nitro, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl or alkaryl. Where the group to be substituted is an alkylgroup the substituent may be ═O. R may be selected from H, C₁₋₆ alkyl,C₃₋₈ cycloalkyl, phenyl, benzyl or phenethyl group, e.g. R is H or C₁₋₃alkyl. Where the moiety is substituted with two or more substituents andtwo of the substituents are adjacent the adjacent substituents may forma C₄₋₈ ring along with the atoms of the moiety on which the substituentsare substituted, wherein the C₄₋₈ ring is a saturated or unsaturatedhydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms or a saturated orunsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms and 1, 2or 3 heteroatoms.

Substituents are only present at positions where they are chemicallypossible, the person skilled in the art being able to decide (eitherexperimentally or theoretically) without inappropriate effort whichsubstitutions are chemically possible and which are not.

Ortho, meta and para substitution are well understood terms in the art.For the absence of doubt, “ortho” substitution is a substitution patternwhere adjacent carbons possess a substituent, whether a simple group,for example the fluoro group in the example below, or other portions ofthe molecule, as indicated by the bond ending in “

”.

“Meta” substitution is a substitution pattern where two substituents areon carbons one carbon removed from each other, i.e. with a single carbonatom between the substituted carbons. In other words there is asubstituent on the second atom away from the atom with anothersubstituent.

For example the groups-below are meta substituted.

“Para” substitution is a substitution pattern where two substituents areon carbons two carbons removed from each other, i.e. with two carbonatoms between the substituted carbons. In other words there is asubstituent on the third atom away from the atom with anothersubstituent. For example the groups below are para substituted.

By “acyl” is meant an organic radical derived from, for example, anorganic acid by the removal of the hydroxyl group, e.g. a radical havingthe formula R—C(O)—, where R may be selected from H, C₁₋₆ alkyl, C₃₋₈cycloalkyl, phenyl, benzyl or phenethyl group, e.g. R is H or C₁₋₃alkyl. In one embodiment acyl is alkyl-carbonyl. Examples of acyl groupsinclude, but are not limited to, formyl, acetyl, propionyl and butyryl.A particular acyl group is acetyl.

Throughout the description the disclosure of a compound also encompassespharmaceutically acceptable salts, solvates and stereoisomers thereof.Where a compound has a stereocentre, both (R) and (S) stereoisomers arecontemplated by the invention, equally mixtures of stereoisomers or aracemic mixture are completed by the present application. Where acompound of the invention has two or more stereocentres any combinationof (R) and (S) stereoisomers is contemplated. The combination of (R) and(S) stereoisomers may result in a diastereomeric mixture or a singlediastereoisomer. The compounds of the invention may be present as asingle stereoisomer or may be mixtures of stereoisomers, for exampleracemic mixtures and other enantiomeric mixtures, and diasteroemericmixtures. Where the mixture is a mixture of enantiomers the enantiomericexcess may be any of those disclosed above. Where the compound is asingle stereoisomer the compounds may still contain otherdiasteroisomers or enantiomers as impurities. Hence a singlestereoisomer does not necessarily have an enantiomeric excess (e.e.) ordiastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. ofabout at least 85%

The invention contemplates pharmaceutically acceptable salts of thecompounds of the invention. These may include the acid addition and basesalts of the compounds. These may be acid addition and base salts of thecompounds. In addition the invention contemplates solvates of thecompounds. These may be hydrates or other solvated forms of thecompound.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulfate, naphthylate,1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate andtrifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts. Hemisalts of acids andbases may also be formed, for example, hemisulfate and hemicalciumsalts. For a review on suitable salts, see “Handbook of PharmaceuticalSalts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of formula (I) may beprepared by one or more of three methods:

(i) by reacting the compound of the invention with the desired acid orbase;

(ii) by removing an acid- or base-labile protecting group from asuitable precursor of the compound of the invention or by ring-opening asuitable cyclic precursor, for example, a lactone or lactam, using thedesired acid or base; or

(iii) by converting one salt of the compound of the invention to anotherby reaction with an appropriate acid or base or by means of a suitableion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in theresulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when said solvent is water.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionised, partially ionised, or non-ionised. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August1975).

Hereinafter all references to compounds of any formula includereferences to salts, solvates and complexes thereof and to solvates andcomplexes of salts thereof.

The compounds of the invention include compounds of a number of formulaas herein defined, including all polymorphs and crystal habits thereof,prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) as hereinafter defined and isotopically-labelledcompounds of the invention.

The present invention also includes all pharmaceutically acceptableisotopically-labelled compounds of the invention wherein one or moreatoms are replaced by atoms having the same atomic number, but an atomicmass or mass number different from the atomic mass or mass number mostcommonly found in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Certain isotopically-labelled compounds, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Before purification, the compounds of the present invention may exist asa mixture of enantiomers depending on the synthetic procedure used. Theenantiomers can be separated by conventional techniques known in theart. Thus the invention covers individual enantiomers as well asmixtures thereof.

For some of the steps of the process of preparation of the compounds ofthe invention, it may be necessary to protect potential reactivefunctions that are not wished to react, and to cleave said protectinggroups in consequence. In such a case, any compatible protecting radicalcan be used. In particular methods of protection and deprotection suchas those described by T. W. GREENE (Protective Groups in OrganicSynthesis, A. Wiley-Interscience Publication, 1981) or by P. J.Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used.All of the above reactions and the preparations of novel startingmaterials used in the preceding methods are conventional and appropriatereagents and reaction conditions for their performance or preparation aswell as procedures for isolating the desired products will be well-knownto those skilled in the art with reference to literature precedents andthe examples and preparations hereto.

Also, the compounds of the present invention as well as intermediatesfor the preparation thereof can be purified according to variouswell-known methods, such as for example crystallization orchromatography.

One or more compounds of the invention may be combined with one or morepharmaceutical agents, for example anti-viral agents, chemotherapeutics,anti-cancer agents, immune enhancers, immunosuppressants, anti-tumourvaccines, anti-viral vaccines, cytokine therapy, or tyrosine kinaseinhibitors, for the treatment of conditions modulated by the inhibitionof Porcn, for example cancer, sarcoma, melanoma, skin cancer,haematological tumors, lymphoma, carcinoma, leukemia, central nervoussystem disorders, inflammation and immunological diseases

The method of treatment or the compound for use in the treatment ofcancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma,carcinoma, leukemia, central nervous system disorders, inflammation andimmunological diseases as defined hereinbefore may be applied as a soletherapy or be a combination therapy with an additional active agent.

The method of treatment or the compound for use in the treatment ofcancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma,carcinoma, leukemia, and central nervous system disorders may involve,in addition to the compound of the invention, conventional surgery orradiotherapy or chemotherapy. Such chemotherapy may include one or moreof the following categories of anti-tumor agents:

(i) antiproliferative/antineoplastic drugs and combinations thereof,such as alkylating agents (for example cis-platin, oxaliplatin,carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard,bendamustin, melphalan, chlorambucil, chlormethine, busulphan,temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman,triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine,stroptozocin and dacarbazine); antimetabolites (for example gemcitabineand antifolates such as fluoropyrimidines like 5-fluorouracil andtegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside,floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabinephosphate, pentostatine, and gemcitabine and hydroxyurea); antibiotics(for example anthracyclines like adriamycin, bleomycin, doxorubicin,daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin andmithramycin); antimitotic agents (for example vinca alkaloids likevincristine, vinblastine, vindesine and vinorelbine and taxoids liketaxol and taxotere and polokinase inhibitors); proteasome inhibitors,for example carfilzomib and bortezomib; interferon therapy; andtopoisomerase inhibitors (for example epipodophyllotoxins like etoposideand teniposide, amsacrine, topotecan, mitoxantrone and camptothecin);bleomcin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (Taxol™), nabpaclitaxel, docetaxel,mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons(especially IFN-α), etoposide, and teniposide;(ii) cytostatic agents such as antiestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5α-reductase suchas finasteride; and navelbene, CPT-II, anastrazole, letrazole,capecitabine, reloxafme, cyclophosphamide, ifosamide, and droloxafine;(iii) anti-invasion agents, for example dasatinib and bosutinib(SKI-606), and metalloproteinase inhibitors, inhibitors of urokinaseplasminogen activator receptor function or antibodies to Heparanase;(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies,for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab,tyrosine kinase inhibitors, for example inhibitors of the epidermalgrowth factor family (for example EGFR family tyrosine kinase inhibitorssuch as gefitinib, erlotinib,6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib) andantibodies to costimulatory molecules such as CTLA-4, 4-IBB and PD-I, orantibodies to cytokines (IL-10, TGF-beta); inhibitors of the hepatocytegrowth factor family; inhibitors of the insulin growth factor family;modulators of protein regulators of cell apoptosis (for example Bcl-2inhibitors); inhibitors of the platelet-derived growth factor familysuch as imatinib and/or nilotinib (AMN107); inhibitors ofserine/threonine kinases (for example Ras/Raf signalling inhibitors suchas farnesyl transferase inhibitors, for example sorafenib, tipifarniband lonafarnib), inhibitors of cell signalling through MEK and/or AKTkinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors,Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor, kinaseinhibitors; aurora kinase inhibitors and cyclin dependent kinaseinhibitors such as CDK2 and/or CDK4 inhibitors; and CCR2, CCR4 or CCR6modulator;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™);thalidomide; lenalidomide; and for example, a VEGF receptor tyrosinekinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib andpazopanib;(vi) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2;(vii) immunotherapy approaches, including for example antibody therapysuch as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) andofatumumab; interferons such as interferon α; interleukins such as IL-2(aldesleukin); interleukin inhibitors for example IRAK4 inhibitors;cancer vaccines including prophylactic and treatment vaccines such asHPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T(Provenge); gp100; dendritic cell-based vaccines (such as Ad.p53 DC);and toll-like receptor modulators for example TLR-7 or TLR-9 agonists;and(viii) cytotoxic agents for example fludaribine (fludara), cladribine,pentostatin (Nipent™);(ix) steroids such as corticosteroids, including glucocorticoids andmineralocorticoids, for example aclometasone, aclometasone dipropionate,aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate,betamethasone, betamethasone dipropionate, betamethasone sodiumphosphate, betamethasone valerate, budesonide, clobetasone, clobetasonebutyrate, clobetasol propionate, cloprednol, cortisone, cortisoneacetate, cortivazol, deoxycortone, desonide, desoximetasone,dexamethasone, dexamethasone sodium phosphate, dexamethasoneisonicotinate, difluorocortolone, fluclorolone, flumethasone,flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide,fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolonecaproate, fluocortolone pivalate, fluorometholone, fluprednidene,fluprednidene acetate, flurandrenolone, fluticasone, fluticasonepropionate, halcinonide, hydrocortisone, hydrocortisone acetate,hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisonebuteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate,meprednisone, methylprednisolone, mometasone paramethasone, mometasonefuroate monohydrate, prednicarbate, prednisolone, prednisone,tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide,triamcinolone alcohol and their respective pharmaceutically acceptablederivatives. A combination of steroids may be used, for example acombination of two or more steroids mentioned in this paragraph;(x) targeted therapies, for example PI3Kd inhibitors, for exampleidelalisib and perifosine; PD-1, PD-L1, PD-L2 and CTL4-A modulators,antibodies and vaccines; IDO inhibitors (such as indoximod); anti-PD-1monoclonal antibodies (such as MK-3475 and nivolumab); anti-PDL1monoclonal antibodies (such as MEDI-4736 and RG-7446); anti-PDL2monoclonal antibodies; and anti-CTLA-4 antibodies (such as ipilimumab);(xi) anti-viral agents such as nucleotide reverse transcriptaseinhibitors (for example, zidovudine, didanosine, zalcitabine, stavudine,lamivudine, abacavir, adefovir diprovoxil, lobucavir, BCH-10652,emitricitabine, beta-L-FD4 (also called 3′-dicleoxy-5-fluoro-cytidine),(−)-beta-D-2,6-diamino-purine dioxolane, and lodenasine), non-nucleosidereverse transcriptase inhibitors (for example, nevirapine, delaviradine,efavirenz, PNU-142721, AG-1549, MKC-442(1-ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmehtyl)-(2,4(1H,3H)pyrimidineone),and (+)-alanolide A and B) and protease inhibitors (for example,saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lasinavir,DMP-450, BMS-2322623, ABT-378 and AG-1 549);(xii) chimeric antigen receptors, anticancer vaccines and arginaseinhibitors.

The method of treatment or the compound for use in the treatment ofinflammation and immunological diseases may involve, in addition to thecompound of the invention, additional active agents. The additionalactive agents may be one or more active agents used to treat thecondition being treated by the compound of the invention and additionalactive agent. The additional active agents may include one or more ofthe following active agents:—

(i) steroids such as corticosteroids, including glucocorticoids andmineralocorticoids, for example aclometasone, aclometasone dipropionate,aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate,betamethasone, betamethasone dipropionate, betamethasone sodiumphosphate, betamethasone valerate, budesonide, clobetasone, clobetasonebutyrate, clobetasol propionate, cloprednol, cortisone, cortisoneacetate, cortivazol, deoxycortone, desonide, desoximetasone,dexamethasone, dexamethasone sodium phosphate, dexamethasoneisonicotinate, difluorocortolone, fluclorolone, flumethasone,flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide,fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolonecaproate, fluocortolone pivalate, fluorometholone, fluprednidene,fluprednidene acetate, flurandrenolone, fluticasone, fluticasonepropionate, halcinonide, hydrocortisone, hydrocortisone acetate,hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisonebuteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate,meprednisone, methylprednisolone, mometasone paramethasone, mometasonefuroate monohydrate, prednicarbate, prednisolone, prednisone,tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide,triamcinolone alcohol and their respective pharmaceutically acceptablederivatives. A combination of steroids may be used, for example acombination of two or more steroids mentioned in this paragraph;(ii) TNF inhibitors for example etanercept; monoclonal antibodies (e.g.infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia),golimumab (Simponi)); fusion proteins (e.g. etanercept (Enbrel)); and5-HT_(2A) agonists (e.g. 2,5-dimethoxy-4-iodoamphetamine, TCB-2,lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide);(iii) anti-inflammatory drugs, for example non-steroidalanti-inflammatory drugs;(iv) dihydrofolate reductase inhibitors/antifolates, for examplemethotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim,pemetrexed, ralitrexed and pralatrexate; and(v) immunosuppressants for example cyclosporins, tacrolimus, sirolimuspimecrolimus, angiotensin II inhibitors (e.g. Valsartan, Telmisartan,Losartan, Irbesatan, Azilsartan, Olmesartan, Candesartan, Eprosartan)and ACE inhibitors e.g. sulfhydryl-containing agents (e.g. Captopril,Zofenopril), dicarboxylate-containing agents (e.g. Enalapril, Ramipril,Quinapril, Perindopril, Lisinopril, Benazepril, Imidapril, Zofenopril,Trandolapril), phosphate-containing agents (e.g. Fosinopril),casokinins, lactokinins and lactotripeptides.

Such combination treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within a therapeutically effective dosage range describedhereinbefore and the other pharmaceutically-active agent within itsapproved dosage range.

Compounds of the invention may exist in a single crystal form or in amixture of crystal forms or they may be amorphous. Thus, compounds ofthe invention intended for pharmaceutical use may be administered ascrystalline or amorphous products. They may be obtained, for example, assolid plugs, powders, or films by methods such as precipitation,crystallization, freeze drying, or spray drying, or evaporative drying.Microwave or radio frequency drying may be used for this purpose.

For the above-mentioned compounds of the invention the dosageadministered will, of course, vary with the compound employed, the modeof administration, the treatment desired and the disorder indicated. Forexample, if the compound of the invention is administered orally, thenthe daily dosage of the compound of the invention may be in the rangefrom 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligramsper kilogram body weight (mg/kg).

A compound of the invention, or pharmaceutically acceptable saltthereof, may be used on their own but will generally be administered inthe form of a pharmaceutical composition in which the compounds of theinvention, or pharmaceutically acceptable salt thereof, is inassociation with a pharmaceutically acceptable adjuvant, diluent orcarrier. Conventional procedures for the selection and preparation ofsuitable pharmaceutical formulations are described in, for example,“Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton,Churchill Livingstone, 1988.

Depending on the mode of administration of the compounds of theinvention, the pharmaceutical composition which is used to administerthe compounds of the invention will preferably comprise from 0.05 to 99%w (percent by weight) compounds of the invention, more preferably from0.05 to 80% w compounds of the invention, still more preferably from0.10 to 70% w compounds of the invention, and even more preferably from0.10 to 50% w compounds of the invention, all percentages by weightbeing based on total composition.

The pharmaceutical compositions may be administered topically (e.g. tothe skin) in the form, e.g., of creams, gels, lotions, solutions,suspensions, or systemically, e.g. by oral administration in the form oftablets, capsules, syrups, powders or granules; or by parenteraladministration in the form of a sterile solution, suspension or emulsionfor injection (including intravenous, subcutaneous, intramuscular,intravascular or infusion); by rectal administration in the form ofsuppositories; or by inhalation in the form of an aerosol.

For oral administration the compounds of the invention may be admixedwith an adjuvant or a carrier, for example, lactose, saccharose,sorbitol, mannitol; a starch, for example, potato starch, corn starch oramylopectin; a cellulose derivative; a binder, for example, gelatine orpolyvinylpyrrolidone; and/or a lubricant, for example, magnesiumstearate, calcium stearate, polyethylene glycol, a wax, paraffin, andthe like, and then compressed into tablets. If coated tablets arerequired, the cores, prepared as described above, may be coated with aconcentrated sugar solution which may contain, for example, gum arabic,gelatine, talcum and titanium dioxide. Alternatively, the tablet may becoated with a suitable polymer dissolved in a readily volatile organicsolvent.

For the preparation of soft gelatine capsules, the compounds of theinvention may be admixed with, for example, a vegetable oil orpolyethylene glycol. Hard gelatine capsules may contain granules of thecompound using either the above-mentioned excipients for tablets. Alsoliquid or semisolid formulations of the compound of the invention may befilled into hard gelatine capsules. Liquid preparations for oralapplication may be in the form of syrups or suspensions, for example,solutions containing the compound of the invention, the balance beingsugar and a mixture of ethanol, water, glycerol and propylene glycol.Optionally such liquid preparations may contain colouring agents,flavouring agents, sweetening agents (such as saccharine), preservativeagents and/or carboxymethylcellulose as a thickening agent or otherexcipients known to those skilled in art.

For intravenous (parenteral) administration the compounds of theinvention may be administered as a sterile aqueous or oily solution.

The size of the dose for therapeutic purposes of compounds of theinvention will naturally vary according to the nature and severity ofthe conditions, the age and sex of the animal or patient and the routeof administration, according to well-known principles of medicine.

Dosage levels, dose frequency, and treatment durations of compounds ofthe invention are expected to differ depending on the formulation andclinical indication, age, and co-morbid medical conditions of thepatient. The standard duration of treatment with compounds of theinvention is expected to vary between one and seven days for mostclinical indications. It may be necessary to extend the duration oftreatment beyond seven days in instances of recurrent infections orinfections associated with tissues or implanted materials to which thereis poor blood supply including bones/joints, respiratory tract,endocardium, and dental tissues.

Throughout the description and claims of this specification, the words“comprise” and “contain” and variations of them mean “including but notlimited to”, and they are not intended to (and do not) exclude othermoieties, additives, components, integers or steps. Throughout thedescription and claims of this specification, the singular encompassesthe plural unless the context otherwise requires. In particular, wherethe indefinite article is used, the specification is to be understood ascontemplating plurality as well as singularity, unless the contextrequires otherwise.

Features, integers, characteristics, compounds, chemical moieties orgroups described in conjunction with a particular aspect, embodiment orexample of the invention are to be understood to be applicable to anyother aspect, embodiment or example described herein unless incompatibletherewith. All of the features disclosed in this specification(including any accompanying claims, abstract and drawings), and/or allof the steps of any method or process so disclosed, may be combined inany combination, except combinations where at least some of suchfeatures and/or steps are mutually exclusive. The invention is notrestricted to the details of any foregoing embodiments. The inventionextends to any novel one, or any novel combination, of the featuresdisclosed in this specification (including any accompanying claims,abstract and drawings), or to any novel one, or any novel combination,of the steps of any method or process so disclosed.

The reader's attention is directed to all papers and documents which arefiled concurrently with or previous to this specification in connectionwith this application and which are open to public inspection with thisspecification, and the contents of all such papers and documents areincorporated herein by reference.

EXAMPLES AND SYNTHESIS

Solvents, reagents and starting materials were purchased from commercialvendors and used as received unless otherwise described. All reactionswere performed at room temperature unless otherwise stated. Compoundidentity and purity confirmations were performed by LCMS UV using aWaters Acquity SQ Detector 2 (ACQ-SQD2# LCA081). The diode arraydetector wavelength was 254 nM and the MS was in positive and negativeelectrospray mode (m/z: 150-800). A 2 μL aliquot was injected onto aguard column (0.2 μm×2 mm filters) and UPLC column (C18, 50×2.1 mm, <2μm) in sequence maintained at 40° C. The samples were eluted at a flowrate of 0.6 mL/min with a mobile phase system composed of A (0.1% (v/v)Formic Acid in Water) and B (0.1% (v/v) Formic Acid in Acetonitrile)according to the gradients outlined in Table 1 below. Retention times RTare reported in minutes.

TABLE 1 Time (min) % A % B Method 1 0 95 5 1.1 95 5 6.1 5 95 7 5 95 7.595 5 8 95 5 Method 2 0 95 5 0.3 95 5 2 5 95 2.6 95 5 3 95 5

NMR was also used to characterise final compounds. NMR spectra wereobtained on a Bruker AVIII 400 Nanobay with 5 mm BBFO probe. Optionally,compound Rf values on silica thin layer chromatography (TLC) plates weremeasured.

Compound purification was performed by flash column chromatography onsilica or by preparative LCMS. LCMS purification was performed using aWaters 3100 Mass detector in positive and negative electrospray mode(m/z: 150-800) with a Waters 2489 UV/Vis detector. Samples were elutedat a flow rate of 20 mL/min on a XBridge™ prep C18 5 μM OBD 19×100 mmcolumn with a mobile phase system composed of A (0.1% (v/v) Formic Acidin Water) and B (0.1% (v/v) Formic Acid in Acetonitrile) according tothe gradient outlined in Table 2 below.

TABLE 2 Time (min) % A % B 0 90 10 1.5 90 10 11.7 5 95 13.7 5 95 14 9090 15 90 90

Chemical names in this document were generated using Elemental Structureto Name Conversion by Dotmatics Scientific Software. Starting materialswere purchased from commercial sources or synthesised according toliterature procedures.

The compounds of the invention may be synthesised by analogy with thefollowing reaction routes:

General Scheme 1

Compounds of the invention could be prepared by analogy with thefollowing route

Biaryl Alpha-Chloroacetamide: Synthesis A

Intermediate 1: 4-(2-methyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine

4-Bromo-7-azaindole (247 mg, 1.25 mmol) and sodium carbonate (352 mg,3.32 mmol) were dissolved in a mixture of ethyl acetate (8 mL) and water(2 mL). Nitrogen was bubbled through the solution for 10 mins, afterwhich (2-methyl-4-pyridinyl)boronic acid (235 mg, 1.72 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]Palladium(II) chloridedichloromethane complex (102.38 mg, 0.13 mmol) were added and the. Thereaction was heated in the MW at 100° C. for 2 hrs. LCMS showsincomplete reaction. A further 30 mg of Catalyst and 100 mg of boronicacid were added and the reaction was heated at 100° C. for 30 mins. Thereaction was filtered through a celite plug washing with EtOAc. Themixture was diluted with sat NH₄Cl solution, the layers separated andthe aqueous phase extracted twice with EtOAc. The combined organicextracts were dried over Na₂SO₄ and reduced in vacuo. The crude materialwas loaded onto a 10 g SCX cartridge and eluted with MeOH and then 1MNH₃ in MeOH. The ammonia layer was reduced in vacuo to afford4-(2-methyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine (280 mg, 1.34 mmol,106.74% yield) as a brown solid.

MS Method 2: RT: 0.79 min, ES⁺ m/z 210.1 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ/ppm: 10.39-10.50 (bs, 1H), 8.96-8.71 (1H, d,J=5.1 Hz, 1H), 8.44-8.47 (d, J=4.9 Hz, 1H), 7.43-7.55 (m, 3H), 7.21-7.25(1H, d, J=4.9 Hz, 1H), 6.71-6.74 (d, J=3.2 Hz, 1H), 2.79 (s, 3H)

Biaryl alpha-chloroacetamide: Synthesis A—Step 1

Intermediate 2: 5-pyrazin-2-ylpyridin-2-amine

A microwave vial with stirrer bar was charged with2-aminopyridine-5-boronic acid pinacol ester (0.95 g, 4.3 mmol)iodopyrazine (777 mg, 3.77 mmol), sodium carbonate (1.20 g, 11.32 mmol)Toluene (5 mL) Water (5 mL) Ethanol (5 mL) and degassed for 10 mins.

Tetrakis(triphenylphosphine)palladium(0) (436 mg, 0.38 mmol) was thenadded and the vial sealed then irradiated at 100° C. for 1 hr. Analysisshowed completion so the reaction mixture was concentrated to dryness,then the residue was suspended in DCM and 1M aqueous HCl was then added.The phases were separated and the aqueous phase was basified with 10%aqueous NaOH until pH-12, The aqueous layer was re-extracted with EtOAcseveral times, dried over sodium sulphate, filtered and concentrated.The resulting solid was triturated with diethyl ether and then filteredgiving 5-pyrazin-2-ylpyridin-2-amine (355 mg, 1.65 mmol, 43.702% yield)as a pink powder.

MS Method 2: RT 0.45 min, ES⁺ m/z 172.9 [M+H]⁺

¹H NMR (400 MHz, DMSO) δ/ppm: 9.08 (s, 1H), 8.71-8.73 (d, J=1.9 Hz, 1H),8.58-8.6 (m, 1H), 8.45-8.47 (d, J=2.5 Hz, 1H), 8.10-8.14 (dd, J=8.7, 2.5Hz, 1H), 6.54-6.57 (d, J=8.7 Hz, 1H), 6.41-6.47 (bs, 2H)

Biaryl alpha-chloroacetamide: Synthesis A—Step 2

Intermediate 3: 2-chloro-N-(5-pyrazin-2-yl-2-pyridyl)acetamide

To a pink suspension of 5-pyrazin-2-ylpyridin-2-amine (355 mg, 2.06mmol), THF (1.5 mL) and N,N-diisopropylethylamine (0.72 mL, 4.12 mmol)was added drop-wise chloroacetyl chloride (0.16 mL, 2.06 mmol) at roomtemperature. The suspension turned black and a large exotherm was givenoff. Analysis of the reaction after 30 mins showed that it was complete.The reaction was diluted with methanol and then concentrated. Theresulting residue was purified by flash column chromatography (12 gSiO₂, 30-100% EtOAc in heptane, then 0-20% MeOH in EtOAc) affording anoff white/brown solid 2-chloro-N-(5-pyrazin-2-yl-2-pyridyl)acetamide(194 mg, 0.78 mmol, 37.84% yield).

MS Method 2: RT 1.10 min, ES⁺ m/z 249 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ/ppm: 8.96-8.99 (d, J=1.5 Hz, 1H), 8.91-8.93(m, 1H), 8.85-8.89 (bs, 1H), 8.58-8.61 (m, 1H), 8.48-8.50 (d, J=2.5 Hz,1H), 8.27-8.35 (m, 2H), 4.17 (s, 2H)

Example 1:2-[4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide

To a solution of 4-(2-methyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine (230mg, 1.1 mmol) in DMF (6 mL) at 0° C. was added sodium hydride, (60%dispersed in mineral oil) (61 mg, 1.54 mmol). The reaction was stirredat 0° C. for 1 hour, after which2-chloro-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (475 mg, 1.91 mmol) wasadded in one portion. The reaction was warmed to room temperature andleft to stir overnight. LCMS indicates incomplete reaction. The reactionwas again cooled to 0° C., and NaH (50 mg) was added. After stirring for1 hour, chloroacetamide (75 mg) was added and the reaction was warmed toroom temperature and stirred over the weekend. The reaction was dilutedwith water and the aqueous phase extracted three times with EtOAc. Thecombined organic extracts were dried over Na₂SO₄ and reduced in vacuo.The crude material purified by flash column chromatography (40 g SiO₂ 0to 100% EtOAc in heptane, followed by 0 to 10% MeOH in EtOAc), howeverthe material was still not

The semi-pure material was dry loaded onto silica and purified again byflash column chromatography (12 g SiO₂, 50% to 100% EtOAc in heptane,followed by 0 to 5% MeOH in EtOAc) to afford2-[4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide(58 mg, 0.14 mmol, 12.52% yield) as a tan solid.

MS Method 1: RT: 2.43 min, ES⁺ m/z 422.1 [M+H]⁻

¹H NMR (400 MHz, DMSO) δ/ppm: 12.27 (s, 1H), 9.31-9.33 (d, J=1.5 Hz,1H), 9.14-9.16 (d, J=1.9 Hz, 1H), 8.72-8.74 (m, 1H), 8.61-8.65 (m, 2H),8.51-8.55 (dd, J=8.7, 2.6 Hz, 1H), 8.35-8.37 (d, J=4.9 Hz, 1H),8.12-8.17 (d, J=8.7 Hz, 1H), 7.73-7.76 (d, J=3.7 Hz, 1H), 7.66 (s, 1H),7.58-7.61 (d, J=5.0 Hz, 1H), 7.34-7.37 (d, J=5.0 Hz, 1H), 6.75-6.77 (d,J=3.5 Hz, 1H), 5.35 (s, 2H), 2.61 (s, 3H).

Example 2

The following compound was prepared by analogy with General Scheme 1substituting 4-Bromo-7-azaindole with the appropriate 5,6-fusedbromo-heteroaryl.

LCMS RT m/z STRUCTURE STRUCTURE NAME (min) MIM

2-[6-methyl-4-(2-methyl-4- pyridyl)pyrrolo[2,3- d]pyrimidin-7-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 2.41 (Method 1) 436.47

General Scheme 2

Further compounds of the invention could be prepared by analogy with thefollowing route

Intermediate 4:2-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-N-(5-pyrazin-2-yl-2-pyridyl)acetamide

6-Chloro-7-deazapurine (139 mg, 0.91 mmol) was dissolved in UMF (2.5 mL)and the solution was cooled to 0° C. NaH (60% dispersed in mineral oil)(54.3 mg, 1.36 mmol) was added and the reaction was stirred at 0° C. for45 mins. The reaction was warmed to room temperature and left to stirfor 15 mins, after which the reaction was again cooled to 0° C. and2-chloro-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (337 mg, 1.36 mmol) wasadded. The reaction was warmed to room temperature and left to stir for16 hours. LCMS showed completion of reaction. The reaction was quenchedby the addition of water and extracted three times with EtOAc. Combinedorganic extracts were dried over Na₂SO₄ and reduced in vacuo. Theproduct was deposited on silica and purified by flash columnchromatography (12 g column, 0 to 100% EtOAc in Heptane then 0 to 10%MeOH in EtOAc) to furnish the product2-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-N-(5-pyrazin-2-yl-2-pyridyl)acetamide(240 mg, 0.60 mmol, 66% yield) as a tan solid.

MS Method 2: RT 3.11 min, ES⁺ m/z 366 [M+H]⁺

¹H NMR (400 MHz, d⁶-DMSO) δ/ppm: 11.3 (s, 1H), 9.32 (d, 1H, J=1.6 Hz),9.14 (dd, 1H, J=2.5, 0.8 Hz), 8.71 (dd, 1H, J=2.5, 1.6 Hz), 8.64 (dd,1H, J=2.5 Hz), 8.52 (dd, 1H, J=8.8, 2.5 Hz), 8.11 (d, 1H, J=8.8 Hz),7.96 (s, 1H), 7.81 (d, 1H, J=3.6 Hz), 6.71 (d, 1H, J=3.6 Hz), 5.34 (s,2H).

Example 3:2-[4-(2-methyl-4-pyridyl)pyrrolo[2,3-d]pyrimidin-7-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide

In a 2.0-5.0 mL microwave vial2-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-N-(5-pyrazin-2-yl-2-pyridyl)acetamide(110 mg, 0.27 mmol) and sodium carbonate (58 mg, 0.55 mmol) weresuspended in 1,4-dioxane (2.5 mL) and water (0.5 mL). Nitrogen wasbubbled through the solution for 10 mins, after which(2-methyl-4-pyridinyl)boronic acid (49 mg, 0.36 mmol) andtetrakis(triphenylphosphine)palladium (0) (32 mg, 0.02 mmol) were added.The vial was capped and the reaction was heated by microwave irradiationat 120° C. for 1 hour. The reaction was observed to be complete by LCMS.The reaction was diluted with sat. NaHCO₃ and extracted three times withEtOAc. Combined organic extracts were dried over Na₂SO₄ and reduced invacuo. The product was dry loaded onto silica and purified by flashcolumn chromatography to afford2-[4-(2-methyl-4-pyridyl)pyrrolo[2,3-d]pyrimidin-7-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide(29 mg, 0.07 mmol, 25% yield) as a grey solid.

MS Method 1: RT 2.30 min, ES⁺ m/z 423 [M+H]⁺

¹H NMR (400 MHz, d⁶-DMSO) δ/ppm: 11.3 (s, 1H), 9.32 (d, 1H, J=1.5 Hz),9.15 (dd, 1H, J=2.4, 0.6 Hz), 8.93 (s, 1H), 8.73 (dd, 1H, J=2.5, 1.5Hz), 8.69 (d, 1H, J=5.2 Hz), 8.64 (d, 1H, J=2.5 Hz), 8.53 (dd, 1H,J=8.8, 2.5 Hz), 8.13 (d, 1H, J=8.8 Hz), 8.00 (bs, 1H), 7.94 (dd, 1H,J=5.2, 1.5 Hz), 7.85 (d, 1H, J=3.8 Hz), 7.08 (s, 1H, J=3.8 Hz), 5.38 (s,2H), 2.64 (s, 3H).

Example 4

The following compounds were prepared by analogy with General Scheme 2substituting 6-Chloro-7-deazapurine with the appropriate 5,6-fusedchloro heteroaryl and (2-methyl-4-pyridinyl)boronic acid with theappropriate heteroaryl boronic acid.

LCMS RT m/z Structure STRUCTURE NAME (min) MIM

2-[4-(2-methyl-4- pyridyl)pyrazolo[3,4- b]pyridin-1-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 2.31 (Method 1) 422.44

2-[4-(2-methyl-4- pyridyl)pyrrolo[2,3- c]pyridin-1-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 1.92 (Method 1) 421.45

2-[4-(2-methylpyrazol-3- yl)pyrazolo[3,4-b]pyridin-1-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 2.85 (Method 1) 411.42

2-[4-(2-methylpyrazol-3- yl)pyrrolo[3,2-c]pyridin-1-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 0.99 (Method 2) 410.43

2-[4-(2-methylpyrazol-3- yl)pyrrolo[2,3-c]pyridin-1-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 2.32 (Method 1) 410.43

2-[4-(2-methylpyrazol-3- yl)pyrrolo[2,3-d]pyrimidin-7-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 2.88 (Method 1) 411.42

2-[4-(2-methyl-4- pyridyl)pyrrolo[3,2- c]pyridin-1-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 2.21 (Method 1) 421.45

N-(5-pyrazin-2-yl-2- pyridyl)-2-[4-[2- (trifluoromethyl)-4-pyridyl]pyrrolo[2,3- d]pyrimidin-7-yl]acetamide 3.56 (Method 1) 476.41

2-[5-cyano-4-(2-methyl-4- pyridyl)pyrrolo[2,3- b]pyridin-1-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 2.60 (Method 1) 446.46

2-[2-methyl-4-(2-methyl-4- pyridyl)pyrrolo[2,3- d]pyrimidin-7-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 2.41 (Method 1) 436.47

2-[2-amino-4-(2-methyl-4- pyridyl)pyrrolo[2,3- d]pyrimidin-7-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 2.24 (Method 1) 437.46

2-[2-chloro-4-(2-methyl-4- pyridyl)pyrrolo[2,3- d]pyrimidin-7-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 1.20 (Method 2) 456.89

2-[5-(2-methyl-4- pyridyl)pyrrolo[2,3- b]pyridin-1-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 2.41 (Method 1) 421.45

2-[5-(2-methyl-4- pyridyl)pyrazolo[3,4- b]pyridin-1-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 2.25 (Method 1) 422.44

2-[4-(2-methyl-4- pyridyl)imidazo[4,5- c]pyridin-1-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 2.24 (Method 1) 422.44

General Scheme 3

Further compounds of the invention could be prepared by analogy with thefollowing route

Intermediate 5: N-(6-bromo-3-pyridyl)-2-chloro-acetamide

5-amino-2-bromopyridine (1.44 g, 8.32 mmol) and DIPEA (2.23 mL, 12.5mmol) were dissolved in DMF (40 mL). Chloroacetyl chloride (0.7 mL, 8.74mmol) was added dropwise and the reaction was left to stir at roomtemperature for 16 hours. LCMS showed that the reaction had completed.The reaction was quenched by the addition of water and extracted threetimes with EtOAc. Combined organic extracts were dried over Na2SO4 andreduced in vacuo. The crude product was deposited onto silica andpurified by flash column chromatography (80 g column, 0 to 100% EtOAc inHeptane) to furnish N-(6-bromo-3-pyridyl)-2-chloro-acetamide (1.52 g,6.09 mmol, 73% yield) as a yellow solid. MS Method 2: RT 1.25 min, ES⁺m/z 250 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ/ppm: 8.45 (d, 1H, J=2.8 Hz), 8.40 (bs, 1H),8.05 (dd, 1H, J=8.6, 2.8 Hz), 7.48 (d, 1H, J=8.6 Hz), 4.22 (s, 2H).

Intermediate 6:N-(6-bromo-3-pyridyl)-2-[4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridine-1-yl]acetamide

4-(2-methyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine (163 mg, 0.78 mmol) wasdissolved in DMF (5 mL) and cooled to 0° C. NaH (60% dispersed inmineral oil) (38 mg, 0.93 mmol) was added and the reaction was stirredat 0° C. for 45 mins. The reaction was warmed to room temperature andstirred for 15 mins, after which the reaction was cooled to 0° C. andN-(6-bromo-3-pyridyl)-2-chloro-acetamide (243 mg, 0.97 mmol) was added.The reaction was warmed to room temperature and left to stir for 16hours. LCMS indicates a small amount of starting material remaining butmainly formation of desired product. The reaction was quenched by theaddition of water and extracted three times with EtOAc. Combined organicextracts were reduced in vacuo. The crude product was deposited ontosilica and the purified by flash column chromatography (12 g column, 0to 100% EtOAc in Heptane then 0 to 10% MeOH in EtOAc) to affordN-(6-bromo-3-pyridyl)-2-[4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridine-1-yl]acetamide(230 mg, 0.54 mmol, 70% yield).

MS Method 2: RT 1.13 min, ES⁺ m/z 423 [M+H]⁺

¹H NMR (400 MHz, d⁶-DMSO) δ/ppm: 10.83 (s, 1H), 8.63-8.61 (m, 2H), 8.35(d, 1H, J=5.0 Hz), 7.98 (dd, 1H, J=8.7, 2.8 Hz), 7.72 (d, 1H, J=3.6 Hz),7.52 (bs, 1H), 7.62 (dd, 1H, J=8.7, 0.4 Hz), 7.58 (dd, 1H, J=5.0, 1.5Hz), 7.35 (d, 1H, J=4.9 Hz), 6.75 (d, 1H, J=3.6 Hz), 5.26 (s, 2H), 2.60(s, 3H).

Example 5:2-[4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridin-1-yl]-N-(6-pyrazin-2-yl-3-pyridyl)acetamide

In a 2.0-5.0 mL microwave vialN-(6-bromo-3-pyridyl)-2-[4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridine-1-yl]acetamide(75 mg, 0.18 mmol) and (tributylstannyl)pyrazine (78 mg, 0.21 mmol) weredissolved in DMF (2.5 mL). Nitrogen was bubbled though the solution for10 mins, after which tetrakis(triphenylphosphine)palladium (0) (21 mg,0.02 mmol) was added, the vial was capped and the reaction mixture washeated by microwave irradiation at 120° C. for 7 hours. LCMS indicatedformation of desired product with a small amount of starting materialremaining. The reaction was diluted with sat. NaHCO₃ solution andextracted three times with EtOAc. Combined organic extracts were reducedin vacuo. The crude product was deposited onto silica and purified byflash column chromatography (12 g column, 0 to 100% EtOAc in Heptanethen 0 to 10% MeOH in EtOAc) to give2-[4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridin-1-yl]-N-(6-pyrazin-2-yl-3-pyridyl)acetamide(7.0 mg, 0.02 mmol, 10% yield) as a white solid.

MS Method 1: RT 2.36 min, ES⁺ m/z 422 [M+H]⁺

¹H NMR (400 MHz, d⁶-DMSO) δ/ppm: 10.94 (s, 1H), 9.49 (d, 1H, J=1.4 Hz),8.93 (d, 1H, J=2.4 Hz), 8.71 (dd, 1H, J=2.4, 1.5 Hz), 8.67 (d, 1H, J=2.5Hz), 8.63 (d, 1H, J=5.1 Hz), 8.37 (d, 1H, J=5.1 Hz), 8.34 (d, 1H, J=8.6Hz), 8.25 (dd, 1H, J=8.6, 2.5 Hz), 7.76 (d, 1H, J=3.7 Hz), 7.66 (bs,1H), 7.59 (d, 1H, J=5.2 Hz), 7.36 (d, 1H, J=4.9 Hz), 6.77 (d, 1H, J=3.7Hz), 5.32 (s, 2H), 2.60 (s, 3H).

Example 6

The following compounds were prepared by analogy with General Scheme 3using the appropriate 5,6-fused chloro heteroaryl and heteroaryl boronicacid.

LCMS RT m/z Structure STRUCTURE NAME (min) MIM

2-[4-(2-methyl-4- pyridyl)pyrrolo[2,3- d]pyrimidin-7-yl]-N-(6-pyrazin-2-yl-3- pyridyl)acetamide 2.28 (Method 1) 422.44

2-[4-(2-methyl-4- pyridyl)pyrazolo[3,4- b]pyridin-1-yl]-N-(6-pyrazin-2-yl-3-pyridyl)acetamide 2.28 (Method 1) 422.44

2-[4-(2-methyl-4- pyridyl)pyrazolo[3,4- d]pyrimidin-1-yl]-N-(6-pyrazin-2-yl-3- pyridyl)acetamide 2.34 (Method 1) 423.43

General Scheme 4

Intermediate 7: 4-chloro-1-tetrahydropyran-2-yl-pyrazolo[34-d]pyrimidine

4-chloro-1H-pyrazolo[3,4-d]pyrimidine (678 mg, 4.39 mmol) andp-toluenesulfonic acid monohydrate (16 mg, 0.09 mmol) were suspended inethyl acetate (25 mL), 3,4-Dihydro-2H-pyran was added and the reactionmixture was heated under reflux for 3 hours. Once all suspended solidshad gone into solution, the solvent was removed in vacuo and the crudeproduct deposited onto silica. The product was purified by flash columnchromatography (12 g column, 0 to 100% EtOAc in Heptane) to furnish4-chloro-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidine (840 mg, 3.52mmol, 80% yield) as a pink solid.

¹H NMR (400 MHz, CDCl₃) δ/ppm: 8.80 (s, 1H), 8.22 (s, 1H), 6.05 (dd, 1H,J=10.4, 2.5 Hz), 4.15-4.10 (m, 1H), 3.85-3.77 (m, 1H), 2.68-2.57 (m,1H), 2.21-2.12 (m, 1H), 2.03-1.95 (m, 1H), 1.95-1.77 (m, 2H), 1.69-1.63(m, 1H).

Intermediate 8:4-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidine

In a 10-20 mL microwave vial4-chloro-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidine (153 mg, 0.64mmol) and sodium carbonate (135 mg, 1.28 mmol) were suspended in1,4-dioxane (4 mL) and water (1 mL). Nitrogen was bubbled through thesolution for 5 mins, after which (2-methyl-4-pyridinyl)boronic acid (105mg, 0.77 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II). CH₂Cl₂ (52mg, 0.06 mmol) were added the vial was capped and the reaction washeated under microwave irradiation at 120° C. for 1 hour. LCMS showedthat the reaction had completed. The reaction was quenched by theaddition of sat. NaHCO₃ and extracted three times with EtOAc. Combinedorganic extracts were reduced in vacuo and deposited onto silica. Thecrude product was purified by flash column chromatography (12 g column,0 to 100% EtOAc in Heptane then 0 to 5% MeOH in EtOAc) to furnish4-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidine(130 mg, 0.44 mmol, 69% yield) as an orange oil.

MS Method 2: RT 1.16 min, ES⁺ m/z 296 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ/ppm: 9.16 (s, 1H), 8.78 (dd, 1H, J=5.2, 0.6Hz), 8.43 (s, 1H), 7.92 (bs, 1H), 7.81 (ddd, 1H, J=5.2, 1.7, 0.6 Hz),6.17 (dd, 1H, J=10.4, 2.6 Hz), 4.20-4.14 (m, 1H), 3.90-3.82 (m, 1H),2.74 (s, 3H), 2.72-2.63 (m, 1H), 2.24-2.15 (m, 1H), 2.07-2.00 (m, 1H),1.87-1.65 (m, 3H).

Intermediate 9: 4-(2-methyl-4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidine

4-(2-methyl-4-pyridyl)-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidine(320 mg, 1.08 mmol) was suspended in 4M HCl in 1,4-dioxane solution (10mL, 40 mmol). The reaction was stirred at room temperature for 16 hours.LCMS showed that the reaction had completed. The reaction was quenchedby addition of sat. NaHCO₃ and extracted three times with EtOAc.Combined organic extracts were reduced in vacuo and deposited ontosilica. The product was purified on by flash column chromatography (12 gcolumn, 0 to 100% EtOAc in Heptane) to afford4-(2-methyl-4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidine (55 mg, 0.26 mmol,24% yield) as a yellow solid.

MS Method 2: RT 0.74 min, ES⁺ m/z 210 [M+H]⁺

¹H NMR (400 MHz, d⁶-DMSO) δ/ppm: 14.35 (bs, 1H), 9.13 (s, 1H), 8.84 (s,1H), 8.72 (d, 1H, J=5.3 Hz), 8.10 (bs, 1H), 8.04 (d, 1H, J=5.3), 2.66(s, 3H).

Example 7:2-[4-(2-methyl-4-pyridyl)pyrazolo[3,4-d]pyrimidin-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide

4-(2-methyl-4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidine (122 mg, 0.58 mmol)was dissolved in DMF (5 mL) and cooled to 0° C. NaH (60% dispersed inmineral oil) (28 mg, 0.69 mmol) was added and the reaction was stirredat 0° C. for 45 mins. The reaction was warmed to room temperature andleft to stir for 15 mins. The reaction was cooled to 0° C. and2-chloro-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (186 mg, 0.75 mmol) wasadded. The reaction was warmed to room temperature and stirred for 3days. LCMS showed the reaction had completed. The reaction was quenchedby the addition of water and extracted three times with EtOAc. Combinedorganic extracts were reduced in vacuo and deposited onto silica. Theproduct was purified by flash column chromatography (25 g column, 0 to100% EtOAc in Heptane then 0 to 10% MeOH in EtOAc) to furnish2-[4-(2-methyl-4-pyridyl)pyrazolo[3,4-d]pyrimidin-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide(15 mg, 0.04 mmol, 6% yield) as a white solid.

MS Method 2: RT 1.08 min, ES⁺ m/z 424 [M+H]⁺

¹H NMR (400 MHz, d⁶-DMSO) δ/ppm: 11.4 (s, 1H), 9.32 (d, 1H, J=1.5 Hz),9.18 (s, 1H), 9.15 (d, 1H, J=2.6 Hz), 8.94 (s, 1H), 8.75-8.72 (m, 2H),8.64 (d, 1H, J=2.5 Hz), 8.53 (dd, 1H, J=8.8, 2.5 Hz), 8.12 (s, 1H), 8.11(d, 1H, J=5.8 Hz), 8.08 (d, 1H, J=5.2 Hz), 5.58 (s, 2H), 2.67 (s, 3H).

Example 8

The following compounds were prepared by analogy with General Scheme 4using the appropriate 5,6-fused chloro heteroaryl and heteroaryl boronicacid.

LCMS RT m/z Structure STRUCTURE NAME (min) MIM

2-[6-(2-methyl-4- pyridyl)purin-9-yl]-N-(5- pyrazin-2-yl-2-pyridyl-acetamide 2.27 (Method 1) 423.43

2-[4-(2-methylpyrazol-3- yl)pyrazolo[3,4- d]pyrimidin-1-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 2.90 (Method 1) 412.41

General Scheme 5

Further compounds of the invention could be prepared by analogy with thefollowing route

Intermediate 9: 4-chloropyrrolo[2,3-b]pyridine-1-yl)-triisopropylsilane

4-Chloro-1H-pyrrolo[2,3-b]pyridine (1.05 g, 6.88 mmol) was dissolved inTHF (50 mL) and cooled to 0° C. NaH (60% dispersed in mineral oil) (1.5g, 10.3 mmol) was added and the reaction was stirred at 0° C. for 1hour. Triisopropylsilyl chloride (2.38 g, 12.4 mmol) was added and thereaction was heated under reflux overnight. TLC (8:2 Heptane/EtOAc)showed consumption of SM (Rf 0.4) and formation of new product spot(0.9). The reaction was quenched with water and extracted three timeswith EtOAc. Combined organic extracts were reduced in vacuo anddeposited onto silica. The product was purified by flash columnchromatography (40 g column, 0 to 20% EtOAc in Heptane) to give(4-chloropyrrolo[2,3-b]pyridine-1-yl)-triisopropylsilane (2.1 g, 6.88mmol, 100% yield).

¹H NMR (400 MHz, CDCl₃) δ/ppm: 8.21 (d, 1H, J=5.4 Hz, 7.39 (d, 1H, J=3.5Hz), 7.12 (d, 1H, J=5.4 Hz), 6.74 (dd, 1H, J=3.5 Hz), 1.93 (hept, 3H,J=7.2 Hz), 1.19 (d, 18H, J=7.2 Hz).

Intermediate 10:(4-chloro-5-fluoro-pyrrolo[2,3-b]pyridine-1-yl)-triisopropylsilane

4-chloropyrrolo[2,3-b]pyridine-1-yl)-triisopropylsilane (290 mg, 0.94mmol) was dissolved in THF (8 mL) and cooled to −78° C. A solution ofs-BuLi was added dropwise and the reaction was stirred at −78° C. for 30mins. A solution of N-fluorobenzenesulfonimide (830 mg, 2.63 mmol) inTHF (3 mL) was added and the reaction was stirred at −78° C. for 1 hour.LCMS was inconclusive as neither starting material nor product can beobserved. The reaction was quenched at −78° C. by addition of sat. NH₄Clsolution and then slowly warmed to room temperature. The reactionmixture was extracted three times with EtOAc and the combined organicextracts were dried over Na₂SO₄ and reduced in vacuo. The crude productwas deposited onto silica and the product purified by flash columnchromatography (12 g column, 0 to 20% EtOAc in Heptane) to give(4-chloro-5-fluoro-pyrrolo[2,3-b]pyridine-1-yl)-triisopropylsilane (180mg, 0.55 mmol, 59% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ/ppm: 8.18 (d, 1H, J=2.0 Hz), 7.41 (d, 1H,J=3.5 Hz), 6.68 (d, 1H, J=3.5 Hz), 1.86 (hept, 3H, J=7.6 Hz), 1.14 (d,18H, J=7.6 Hz).

Intermediate 11:[5-fluoro-4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridine-1-yl-triisopropylsilane

In a 2.0-5.0 mL microwave vial(4-chloro-5-fluoro-pyrrolo[2,3-b]pyridine-1-yl)-triisopropylsilane (180mg, 0.55 mmol) and potassium phosphate tribasic (233 mg, 1.10 mmol) weresuspended in 1,4-dioxane (4 mL) and water (1 mL). Nitrogen was bubbledthrough the solution for 10 mins, after which 2-methylpyridine-4-boronicacid (180 mg, 1.31 mmol), tricyclohexylphosphine (15 mg, 0.06 mmol) andtris(dibenzylideneacetone)dipalladium (0) (34 mg, 0.04 mmol) were added.The vial was capped and reaction was heated by microwave irradiation at120° C. for 1 hour. LCMS indicated completion of reaction. The reactionwas diluted with sat. NaHCO₃ and extracted three times with EtOAc.Combined organic extracts were reduced in vacuo and deposited ontosilica. The crude product was purified by flash column chromatography(12 g, 0 to 50% EtOAc in Heptane) to furnish[5-fluoro-4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridine-1-yl-triisopropylsilane(136 mg, 0.35 mmol, 64% yield) as a colourless oil.

MS Method 2: RT 2.48 min, ES⁺ m/z 384 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ/ppm: 8.66 (d, 1H, J=5.2 Hz), 8.24 (d, 1H,J=2.9 Hz), 7.50 (bs, 1H), 7.44-7.41 (m, 2H), 6.59 (d, 1H, J=3.6 Hz),2.68 (s, 3H), 1.87 (hept, 3H, J=7.7 Hz), 1.16 (d, 18H, J 15=7.7 Hz).

Intermediate 12:5-fluoro-4-(2-methyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine

[5-fluoro-4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridine-1-yl-triisopropylsilane(136 mg, 0.35 mmol) was dissolved in THF (3.5 mL) and a 1M solution oftetrabutylammonium fluoride in THF (0.43 mL, 0.43 mmol) was added. Thereaction was stirred at room temperature for 2 hours, after which thereaction was observed to be complete by LCMS. The reaction was dilutedwith water and extracted three times with EtOAc. Combined organicextracts were dried over Na₂SO₄ and reduced in vacuo to yield5-fluoro-4-(2-methyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.35mmol, 80% yield) as a yellow solid.

MS Method 2: RT 0.90 min, ES⁺ m/z 228 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ/ppm: 9.41 (bs, 1H), 8.69 (d, 1H, J=5.2 Hz),8.32 (d, 1H, J=3.1 Hz), 7.50 (bs, 1H), 7.47 (dd, 1H, J=3.5, 2.5 Hz),7.44 (d, 1H, J=3.1 Hz), 6.56 (dd, 1H, J=3.5, 2.0 Hz), 2.69 (s, 3H).

Example 9:2-[5-fluoro-4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide

5-fluoro-4-(2-methyl-4-pyridyl)-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.35mmol) was dissolved in DMF (4 mL) and cooled to 0° C. NaH (60% dispersedin mineral oil) (17 mg, 0.42 mmol) was added and the reaction wasstirred at 0° C. for 45 mins, after which the reaction was warmed toroom temperature and stirred for 15 mins. The reaction was cooled to 0°C. and 2-chloro-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (114 mg, 0.46mmol) was added. The reaction was warmed to room temperature and left tostir for 16 hours. LCMS showed a small amount of starting materialremaining and also formation of desired product. The reaction wasquenched by the addition of water and extracted three times with EtOAc.Combined organic extracts were reduced in vacuo and deposited ontosilica. The product was purified by flash column chromatography (12 gcolumn, 0 to 100% EtOAc in Heptane then 0-10% MeOH in EtOAc). Thepurified product was then purified by prep HPLC to give the purifiedproduct2-[5-fluoro-4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide(10 mg, 0.03 mmol, 6% yield).

MS Method 1: RT 2.58 min, ES⁺ m/z 440 [M+H]⁺

¹H NMR (400 MHz, d⁶-DMSO) δ/ppm: 11.28 (s, 1H), 9.32 (d, 1H, J=1.5 Hz),9.15 (dd, 1H, J=2.5, 0.7 Hz), 8.73 (dd, 1H, J=2.5, 1.5 Hz), 8.66 (d, 1H,J=5.2 Hz), 8.64 (d, 1H, J=2.5 Hz), 8.53 (dd, 1H, J=8.8, 2.5 Hz), 8.38(d, 1H, J=2.9 Hz), 8.14 (d, 1H, J=8.8 Hz), 7.79 (d, 1H, J=3.5 Hz), 7.56(s, 1H), 7.49 (d, 1H, J=5.2 Hz), 6.56 (d, 1H, J=3.5 Hz), 5.34 (s, 2H),2.60 (s, 3H).

Example 10

The following compound was prepared by analogy with General Scheme 5using the appropriate 5,6-fused chloro heteroaryl.

LCMS RT m/z Structure STRUCTURE NAME (min) MIM

2-[5-methyl-4-(2-methyl-4- pyridyl)pyrrolo[2,3- b]pyridin-1-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 2.50 (Method 1) 435.45

General Scheme 6

Further compounds of the invention could be prepared by analogy with thefollowing route

Intermediate 13:2-(4-chloropyrrolo[2,3-b]pyridin-1-yl)-N-(5-pyrazin-2-yl-2-pyridyl)acetamide

2-chloro-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (708 mg, 2.85 mmol) andpotassium carbonate (1132 mg, 8.19 mmol) were added to a solution of4-chloro-1H-pyrrolo[2,3-b]pyridin (250 mg, 1.64 mmol) in DMF (70 mL),the reaction mixture was heated to 60° C. overnight. LCMS analysisdemonstrated the formation of the desired product. The reaction mixturewas concentrated to dryness, the resulting residue taken up in DCM andsodium bicarbonate was added. The phases were separated and the aqueousextracted with DCM. The combined organic layers were washed with brine,dried over sodium sulphate and solvent was removed under reducedpressure. The crude residue was purified by column chromatography (40 gSiO₂, 0-10% MeOH in DCM) like fractions were combined and solventremoved under reduced pressure to yield2-(4-chloropyrrolo[2,3-b]pyridin-1-yl)-N-(5-pyrazin-2-yl-2-pyridyl)acetamide(350 mg, 0.96 mmol, 59% yield) as a cream solid.

MS Method 1: RT 3.52 min, ES⁺ m/z 365.1/367.0 [M+H]⁺

¹H NMR (400 MHz, CDCl₃) δ/ppm: 9.00-9.02 (d, J=1.5 Hz, 1H), 8.90-8.93(m, 1H), 8.64-8.67 (m, 1H), 8.55-8.57 (d, J=2.4 Hz, 1H), 8.30-8.39 (m,3H), 7.40-7.43 (d, J=3.6 Hz, 1H), 7.23-7.25 (d, J=5.3 Hz, 1H), 6.74-6.76(d, J=3.6 Hz, 1H), 5.23 (s, 2H).

Example 11:2-[4-(1-piperidyl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide

Triethylamine (0.19 mL, 1.37 mmol) and piperidine (0.14 mL, 1.37 mmol)were added to a solution of2-(4-chloropyrrolo[2,3-b]pyridin-1-yl)-N-(5-pyrazin-2-yl-2-pyridyl)acetamide(100 mg, 0.27 mmol) in NMP (2 mL). The reaction was subjected tomicrowave radiation at 180° C. for 4 hrs. LCMS analysis demonstrated thereaction had formed the desired product ion. Brine and DCM were added tothe reaction mixture, and the layers separated. The aqueous wasextracted with DCM (×3), the combined organic layers were dried oversodium sulphate and solvent removed under reduced pressure. The cruderesidue was purified by column chromatography (0-10% MeOH in DCM) likefractions were combined and solvent removed under reduced pressure. Thecrude residue was taken up in DMSO:MeCN:H2O (8:1:1) and purified byreverse phase preparative HPLC (eluting with H₂O and MeCN plus 0.1%formic acid). Like fraction were combined and passed through an SCXcartridge, the cartridge was eluted with MeOH and then NH₃/MeOH. TheNH₃/MeOH fractions were combined and solvent removed under reducedpressure to yield2-[4-(1-piperidyl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide(3 mg, 0.0073 mmol, 2.6% yield) as a colourless solid.

MS Method 1: RT 2.81 min, ES⁺ m/z 414.1[M+H]⁺

¹H NMR (400 MHz, D6-DMSO) δ/ppm: 11.13 (bs, 1H), 9.30-9.32 (d, J=1.5 Hz,1H), 9.12-9.14 (m, 1H), 8.71-8.74 (m, 1H), 8.63-8.64 (d, J=2.6 Hz, 1H),8.50-8.54 (dd, J=2.6, 8.9 Hz, 1H), 8.11-8.16 (d, J=8.7 Hz, 1H),7.91-7.94 (d, J=5.5 Hz, 1H), 7.33-7.35 (d, J=3.5 Hz, 1H), 6.48-6.50 (d,J=3.7 Hz, 1H), 6.44-6.47 (d, J=5.5 Hz, 1H), 5.19 (s, 2H), 3.40-3.46 (m,4H), 1.62-1.71 (m, 6H).

Example 12

The following compounds were prepared using the method described ingeneral scheme 6, replacing piperidine with the appropriate saturatedamine.

LCMS RT m/z Structure STRUCTURE NAME (min) MIM

2-[4-(3,5-dimethylpiperazin-1- yl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 1.83 (Method 1) 443.1

2-[4-(4-methylpiperazin-1- yl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5-pyrazin-2-yl-2- pyridyl)acetamide 1.64 (Method 1) 429.1

Dual-Cell β-Catenin Reporter Assay

Mouse L cells transfected to constitutively produce biologically activemurine Wnt-3a, referred to as L-Wnt cells, were purchased from theAmerican Type Culture Collection, ATCC, Manassas, Va. (ATCC). Thesecells were cultured in DMEM supplemented with 10% FCS (Gibco/Invitrogen,Carlsbad, Calif.), 1% geneticin and 1% sodium pyruvate (Sigma) at 37° C.with 5% CO₂. The cells were seeded into 96 well plates and treated withserial dilutions of compound diluted to 0.1% DMSO concentration. After24 hours, cell supernatants were transferred to a 96 well platepreviously seeded with Leading Light® Wnt Reporter Cells, stablytransfected with a luciferase gene under control of Wnt pathway responseelements. After a further 24 hours, cells are treated with One-gloluciferase assay system (Promega, Madison, Wis.) and the luminescentsignal read by envision. The IC₅₀ of the compound is determined as theconcentration that reduces the induced luciferase signal to 50% of theDMSO control.

The results of the in vitro biological data for certain compounds of theinvention are given in the table below. The table shows a group for eachcompound based on the IC50 value of each compound as “+”, “++” and“+++”. The category “+” refers to compounds with an IC50 of >5 nM. Thecategory “++” refers to compounds with an IC50 of 1 nM to 5 nM. Thecategory “+++” refers to compounds with an IC50 of <1 nM.

ID No. Compound Name IC50 (nM) 12-[5-methyl-4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5- ***pyrazin-2-yl-2-pyridyl)acetamide 22-[5-fluoro-4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5- ***pyrazin-2-yl-2-pyridyl)acetamide 32-[5-(2-methyl-4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]-N-(5-pyrazin- ***2-yl-2-pyridyl)acetamide 42-[4-(2-methylpyrazol-3-yl)pyrrolo[3,2-c]pyridin-1-yl]-N-(5-pyrazin- **2-yl-2-pyridyl)acetamide 52-[5-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5-pyrazin-2- ***yl-2-pyridyl)acetamide 62-[4-(2-methylpyrazol-3-yl)pyrazolo[3,4-b]pyridin-1-yl]-N-(5- *pyrazin-2-yl-2-pyridyl)acetamide 72-[4-(2-methylpyrazol-3-yl)pyrrolo[2,3-c]pyridin-1-yl]-N-(5-pyrazin- **2-yl-2-pyridyl)acetamide 82-[2-amino-4-(2-methyl-4-pyridyl)pyrrolo[2,3-d]pyrimidin-7-yl]-N- ***(5-pyrazin-2-yl-2-pyridyl)acetamide 92-[5-cyano-4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyrimidin-1-yl]-N-(5- ***pyrazin-2-yl-2-pyridyl)acetamide 102-[2-methyl-4-(2-methyl-4-pyridyl)pyrrolo[2,3-d]pyrimidin-7-yl]-N- ***(5-pyrazin-2-yl-2-pyridyl)acetamide 112-[4-(2-methylpyrazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]-N-(5- ***pyrazin-2-yl-2-pyridyl)acetamide 122-[2-chloro-4-(2-methyl-4-pyridyl)pyrrolo[2,3-d]pyrimidin-7-yl]-N- ***(5-pyrazin-2-yl-2-pyridyl)acetamide 132-[6-methyl-4-(2-methyl-4-pyridyl)pyrrolo[2,3-d]pyrimidin-7-yl]-N- *(5-pyrazin-2-yl-2-pyridyl)acetamide 142-[4-(2-methyl-4-pyridyl)pyrazolo[3,4-d]pyrimidin-1-yl]-N-(6- **pyrazin-2-yl-3-pyridyl)acetamide 152-[4-(2-methyl-4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]-N-(6-pyrazin- **2-yl-3-pyridyl)acetamide 162-[4-(2-methyl-4-pyridyl)pyrrolo[2,3-d]pyrimidin-7-yl]-N-(6-pyrazin- *2-yl-3-pyridyl)acetamide 172-[4-(2-methyl-4-pyridyl)pyrrolo[2,3-d]pyridin-1-yl]-N-(6-pyrazin-2- **yl-3-pyridyl)acetamide 182-[4-(2-methylpyrazol-3-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-N-(5- **pyrazin-2-yl-2-pyridyl)acetamide 192-[6-(2-methyl-4-pyridyl)purin-9-yl]-N-(5-pyrazin-2-yl-2- *pyridyl)acetamide 202-[4-(2-methyl-4-pyridyl)imidazo[4,5-c]pyridin-1-yl]-N-(5-pyrazin- **2-yl-2-pyridyl)acetamide 21N-(5-pyrazin-2-yl-2-pyridyl)-2-[4-[2-(trifluoromethyl)-4- ***pyridyl]pyrrolo[2,3-d]pyrimidin-7-yl]acetamide 222-[4-(2-methyl-4-pyridyl)pyrazolo[3,4-d]pyrimidin-1-yl]-N-(5- ***pyrazin-2-yl-2-pyridyl)acetamide 232-[4-(2-methyl-4-pyridyl)pyrrolo[3,2-c]pyridin-1-yl]-N-(5-pyrazin-2- ***yl-2-pyridyl)acetamide 242-[4-(2-methyl-4-pyridyl)pyrrolo[2,3-c]pyridin-1-yl]-N-(5-pyrazin-2- ***yl-2-pyridyl)acetamide 252-[4-(2-methyl-4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]-N-(5-pyrazin- ***2-yl-2-pyridyl)acetamide 262-[4-(2-methyl-4-pyridyl)pyrrolo[2,3-d]pyrimidin-7-yl]-N-(5-pyrazin- ***2-yl-2-pyridyl)acetamide 272-[4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5-pyrazin-2- ***yl-2-pyridyl)acetamide 282-[4-(4-methylpiperazin-1-yl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5- *pyrazin-2-yl-2-pyridyl)acetamide 292-[4-(3,5-dimethylpiperazin-1-yl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5- *pyrazin-2-yl-2-pyridyl)acetamide 302-[4-(1-piperidyl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5-pyrazin-2-yl-2- nvpyridyl)acetamide 312-[4-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5-pyrazin- ***2-yl-2-pyridyl)acetamide

Specific IC₅₀ values for a selection of compounds of the invention aregiven below.

ID no. Compound IC50 (nM) 272-[4-(2-methyl-4-pyridyl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5-pyrazin- 0.672-yl-2-pyridyl)acetamide 32-[5-(2-methyl-4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]-N-(5- 0.36pyrazin-2-yl-2-pyridyl)acetamide 102-[2-methyl-4-(2-methyl-4-pyridyl)pyrrolo[2,3-d]pyrimidin-7-yl]- 0.32N-(5-pyrazin-2-yl-2-pyridyl)acetamide 232-[4-(2-methyl-4-pyridyl)pyrrolo[3,2-c]pyridin-1-yl]-N-(5-pyrazin- 0.432-yl-2-pyridyl)acetamide 312-[4-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-1-yl]-N-(5- 0.89pyrazin-2-yl-2-pyridyl)acetamide

Specificity Immunoprecipitation

L-Wnt cells can be assessed by treatment with alkanyl-palmitate andseveral concentrations of compound. After 24 hours cell lysates could bewashed in PBS (SOURCE) and collected in ice cold lysis buffer (LYSISBUFFER). Dynabeads (SOURCE) can be incubated with anti-wnt-3a antibody(Abcam) for 20 minutes and incubated with lysates for an hour. Beads canbe isolated by magnet and the unbound faction retained. Click chemistrycan be performed on samples using Click-iT® protein buffer kit (Lifetechnologies), following the protocol provided, to conjugate biotin toalkanyl palmitate. Elutes can be separated from the samples by magnetand the resulting samples boiled for 20 minutes to dissociate theconjugates. Beads can be removed and the elutes and unbound fraction canbe run by polyacrylamide gel electrophoresis, transferred to a membraneand stained for biotin using streptavidin-horseradish peroxidase and fortotal Wnt by specific antibody.

Cell Death Assay

Cells in growth media (DMEM, 10% FCS) can be treated with a serialdilution of compound diluted to 0.1% DMSO for 72 hours. Viable cellnumber was measured by the ability to reduce resazurin to resorufinwhich was detected by fluorescence emission at 590 nm.

Foci Formation Assay

Capan-2 cells can be seeded onto 6 well plates in standard growth mediaand treated with serial dilutions of compound. Cell media was changedevery four days with fresh compound added. After ten days' growth, cellscan be fixed on methanol and treated with crystal violet to visualise.Area covered by cell colonies was detected by Operetta and analysedusing Columbus software.

The invention claimed is:
 1. A pharmaceutical formulation comprising acompound of formula (VIa) and a pharmaceutically acceptable excipient:

wherein het¹ represents a substituted or unsubstituted 9 memberedbicyclic heteroaryl group comprising a 5 membered ring, wherein the 5membered ring comprises 1 or 2 nitrogen atoms, and a 6 membered ring,wherein the 6 membered ring comprises 1 or 2 nitrogen atoms, and whensubstituted the ring system is substituted with 1, 2, or 3 groupsindependently selected at each occurrence from the group consisting ofhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —OR^(A2), —NR^(A2)R^(B2), —CN,SO₂R^(A2), and C₃₋₆ cycloalkyl; het² represents an aromatic, saturatedor unsaturated 6 membered heterocyclic ring which is unsubstituted orsubstituted, and when substituted the ring is substituted with 1, 2 or 3groups independently selected at each occurrence from the groupconsisting of halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —OR^(A1),—NR^(A1)R^(B1), —CN, —NO₂, —NR^(A1)C(O)R^(B1), —C(O)NR^(A1)R^(B1),—NR^(A1)SO₂R^(B1), —SO₂NR^(A1)R^(B1), —SO₂R^(A1), —C(O)R^(A1),—C(O)OR^(A1) and C₃₋₆ cycloalkyl; R³ is selected from the groupconsisting of H, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₃₋₆ cycloalkyl; R⁴ isindependently selected at each occurrence from the group consisting ofhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —CN, —OR^(A4), —NR^(A4)R^(B4),—SO₂R^(A4), C₃₋₆ cycloalkyl and C₃₋₆ halocycloalkyl; n is 0, 1 or 2; andR^(A1), R^(B1), R^(A2), R^(B2), R^(A4) and R^(B4) are at each occurrenceindependently selected from the group consisting of H, C₁₋₄ alkyl, C₁₋₄haloalkyl.
 2. The pharmaceutical formulation of claim 1, wherein het¹represents a substituted or unsubstituted 9 membered bicyclic heteroarylgroup comprising a 5 membered ring, wherein the 5 membered ringcomprises 1 nitrogen atom, and a 6 membered ring, wherein the 6 memberedring comprises 1 nitrogen atom.
 3. The pharmaceutical formulation ofclaim 2, wherein het¹ represents a group selected from the groupconsisting of unsubstituted or substituted: azaindole and azaisoindole.4. The pharmaceutical formulation of claim 3, wherein het¹ representsunsubstituted or substituted azaindole.
 5. The pharmaceuticalformulation of claim 4, wherein het¹ represents 5-azaindole, 6-azaindoleor 7-azaindole.
 6. The pharmaceutical formulation of claim 1, whereinhet² represents a group selected from the group consisting ofsubstituted or unsubstituted: pyridine, pyrazine, pyrimidine andpyridazine.
 7. The pharmaceutical formulation of claim 6, wherein het²is unsubstituted or substituted pyridine.
 8. The pharmaceuticalformulation of claim 7, wherein het² is substituted pyridine.
 9. Thepharmaceutical formulation of claim 8, wherein het² is substituted with1, 2 or 3 groups selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,—OR^(A1), —NR^(A1)R^(B1), —CN and C₃₋₆ cycloalkyl.
 10. Thepharmaceutical formulation of claim 8, wherein het² is substituted with1, 2 or 3 groups independently selected at each occurrence from thegroup consisting of fluoro, chloro, methyl, ethyl, trifluoromethyl,trifluoroethyl, CN and OCF₃.
 11. The pharmaceutical formulation of claim8, wherein het² is substituted with 1 or 2 groups independently selectedat each occurrence from the group consisting of methyl andtrifluoromethyl.
 12. The pharmaceutical formulation of claim 1, whereinhet¹ is unsubstituted azaindole and het² is substituted pyridine. 13.The pharmaceutical formulation of claim 1, wherein n is
 0. 14. Thepharmaceutical formulation of claim 1, wherein R³ is H or methyl. 15.The pharmaceutical formulation of claim 1, wherein R³ is H.
 16. Thepharmaceutical formulation of claim 1, wherein R⁴ is independentlyselected at each occurrence from the group consisting of halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, —CN, OR^(A4) and —NR^(A4)R^(B4).
 17. Thepharmaceutical formulation of claim 16, wherein R⁴ is independentlyselected at each occurrence from the group consisting of H, chloro,fluoro, methyl, ethyl, trifluoromethyl, trifluoroethyl, —OCF₃, —OH,—OMe, -OEt, —NH₂, —NHMe and —NMe₂.
 18. The pharmaceutical formulation ofclaim 1, wherein the compound is selected from the group consisting of:


19. A method of treatment of a condition mediated by the Wnt signallingpathway selected from the group consisting of cancer, sarcoma, melanoma,skin cancer, haematological tumours, lymphoma, carcinoma, and leukaemia,wherein the method comprises administering to a patient in need thereofa therapeutic amount of a pharmaceutical formulation comprising acompound of formula (VIa) and a pharmaceutically acceptable excipient:

wherein het¹ represents a substituted or unsubstituted 9 memberedbicyclic heteroaryl group comprising a 5 membered ring, wherein the 5membered ring comprises 1 or 2 nitrogen atoms, and a 6 membered ring,wherein the 6 membered ring comprises 1 or 2 nitrogen atoms, and whensubstituted the ring system is substituted with 1, 2, or 3 groupsindependently selected at each occurrence from the group consisting ofhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —OR^(A2), —NR^(A2)R^(B2), —CN,—SO₂R^(A2), and C₃₋₆ cycloalkyl; het² represents an aromatic, saturatedor unsaturated 6 membered heterocyclic ring which is unsubstituted orsubstituted, and when substituted the ring is substituted with 1, 2 or 3groups independently selected at each occurrence from the groupconsisting of halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —OR^(A1),—NR^(A1)R^(B1), —CN, —NO₂, —NR^(A1)C(O)R^(B1), —C(O)NR^(A1)R^(B1),—NR^(A1)SO₂R^(B1), —SO₂NR^(A1)R^(B1), —SO₂R^(A1), —C(O)R^(A1),—C(O)OR^(A1) and C₃₋₆ cycloalkyl; R³ is selected from the groupconsisting of H, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₃₋₆ cycloalkyl; R⁴ isindependently selected at each occurrence from the group consisting ofhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —CN, —OR^(A4), —NR^(A4)R^(B4),—SO₂R^(A4), C₃₋₆ cycloalkyl and C₃₋₆ halocycloalkyl; n is 0, 1 or 2; andR^(A1), R^(B1), R^(A2), R^(B2), R^(A4) and R^(B4) are at each occurrenceindependently selected from the group consisting of H, C₁₋₄ alkyl, C₁₋₄haloalkyl.
 20. A method of treatment of a condition mediated by the Wntsignalling pathway selected from the group consisting of esophagealsquamous cell carcinoma, gastric cancer, glioblastomas, astrocytomas,retinoblastoma, osteosarcoma, chondosarcoma, Ewing's sarcoma,rhabdomysarcoma, Wilm's tumour, basal cell carcinoma, non-small celllung cancer, brain tumour, hormone refractory prostate cancer, prostatecancer, metastatic breast cancer, breast cancer, metastatic pancreaticcancer, pancreatic cancer, colorectal cancer, cervical cancer, head andneck squamous cell carcinoma, and cancer of the head neck, wherein themethod comprises administering to a patient in need thereof atherapeutic amount of a pharmaceutical formulation of claim
 1. 21. Amethod of treatment of a condition mediated by the Wnt signallingpathway selected from the group consisting of skin fibrosis, idiopathicpulmonary fibrosis, renal interstitial fibrosis, liver fibrosis,proteinuria, kidney graft rejection, osteoarthritis, Parkinson'sdisease, cystoid macular edema, uveitis associated cystoid macularedema, retinopathy, diabetic retinopathy and retinopathy of prematurity,wherein the method comprises administering to a patient in need thereofa therapeutic amount of a pharmaceutical formulation of claim
 1. 22. Acompound of formula (Ma):

wherein het¹ represents unsubstituted azaindole; het² is a 5 or 6membered heterocyclic ring which may be unsubstituted or substituted,and when substituted the ring is substituted with 1, 2 or 3 groupsindependently selected at each occurrence from the group consisting ofhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —OR^(A1), —NR^(A1)R^(B1), —CN, —NO₂,—NR^(A1)C(O)R^(B1), —C(O)NR^(A1)R^(B1), —NR^(A1)SO₂R^(B1),—SO₂NR^(A1)R^(B1), —SO₂R^(A1), —C(O)R^(A1), —C(O)OR^(A1) and C₃₋₆cycloalkyl; het³ is a 6 membered heterocyclic ring which may beunsubstituted or substituted, and when substituted the ring issubstituted with 1, 2 or 3 groups independently selected at eachoccurrence from the group consisting of halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, —OR^(A1), —NR^(A1)R^(B1), —CN, —NO₂, —NR^(A1)C(O)R^(B1),—C(O)NR^(A1)R^(B1), —NR^(A1)SO₂R^(B1), —SO₂NR^(A1)R^(B1), —SO₂R^(A1),—C(O)R^(A1), —C(O)OR^(A1) and C₃₋₆ cycloalkyl; R³ is selected from thegroup consisting of H, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₃₋₆ cycloalkyl;R⁴ is independently selected at each occurrence from the groupconsisting of halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —CN, —OR^(A4),—NR^(A4)R^(B4), —SO₂R^(A4), C₃₋₆ cycloalkyl and C₃₋₆ halocycloalkyl; nis 0, 1 or 2; and R^(A1), R^(B1), R^(A2), R^(B2), R^(A4) and R^(B4) areat each occurrence independently selected from the group consisting ofH, C₁₋₄ alkyl, and C₁₋₄ haloalkyl.
 23. The compound of claim 22, whereinhet² represents a ring selected from the group consisting ofunsubstituted or substituted: pyrazole, imidazole, pyridine, pyrazine,pyrimidine, pyridazine, pyran, tetrahydropyran, dihydropyran,piperidine, piperazine, morpholine, thiomorpholine, oxazine, dioxine,dioxane, thiazine, oxathiane and dithiane.
 24. The compound of claim 23,wherein het² represents a ring selected from the group consisting ofunsubstituted or substituted: pyrazole, imidazole, pyridine,tetrahydropyran, dihydropyran, piperidine, piperazine and morpholine.25. The compound of claim 24, wherein het² is unsubstituted orsubstituted with 1 or 2 groups selected from the group consisting offluoro, chloro, methyl, ethyl, trifluoromethyl, trifluoroethyl, —CN and—OCF₃.
 26. The compound of claim 22, wherein het³ represents an aromatic6 membered heterocyclic ring which is unsubstituted or substituted andcomprises at least one nitrogen atom.
 27. The compound of claim 22,wherein het³ represents a ring selected from the group consisting ofunsubstituted or substituted: pyrimidine, pyrazine, and pyridazine. 28.The compound of claim 27, wherein het³ represents a ring selected fromthe group consisting of unsubstituted pyrimidine, pyrazine andpyridazine.
 29. The compound of claim 22, wherein n is
 0. 30. Thecompound of claim 22, wherein R³ is H or methyl.
 31. The compound ofclaim 22, wherein R⁴ is independently selected at each occurrence fromthe group consisting of halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —CN, OR^(A4)and —NR^(A4)R^(B4).
 32. The compound of claim 22, wherein the compoundis selected from the group consisting of:


33. A method of treatment of a condition mediated by the Wnt signallingpathway selected from the group consisting of cancer, sarcoma, melanoma,skin cancer, haematological tumours, lymphoma, carcinoma, and leukaemia,wherein the method comprises administering to a patient in need thereofa therapeutic amount of a compound of formula (Ma) and apharmaceutically acceptable excipient:

wherein het¹ represents unsubstituted azaindole; het² is a 5 or 6membered heterocyclic ring which may be unsubstituted or substituted,and when substituted the ring is substituted with 1, 2 or 3 groupsindependently selected at each occurrence from the group consisting ofhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —OR^(A1), —NR^(A1)R^(B1), —CN, —NO₂,—NR^(A1)C(O)R^(B1), —C(O)NR^(A1)R^(B1), —NR^(A1)SO₂R^(B1),—SO₂NR^(A1)R^(B1), —SO₂R^(A1), —C(O)R^(A1), —C(O)OR^(A1) and C₃₋₆cycloalkyl; het³ is a 6 membered heterocyclic ring which may beunsubstituted or substituted, and when substituted the ring issubstituted with 1, 2 or 3 groups independently selected at eachoccurrence from the group consisting of halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, —OR^(A1), —NR^(A1)R^(B1), —CN, —NO₂, —NR^(A1)C(O)R^(B1),—C(O)NR^(A1)R^(B1), —NR^(A1)SO₂R^(B1), —SO₂NR^(A1)R^(B1), —SO₂R^(A1),—C(O)R^(A1), —C(O)OR^(A1) and C₃₋₆ cycloalkyl; R³ is selected from thegroup consisting of H, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₃₋₆ cycloalkyl;R⁴ is independently selected at each occurrence from the groupconsisting of halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —CN, —OR^(A4),—NR^(A4)R^(B4), —SO₂R^(A4), C₃₋₆ cycloalkyl and C₃₋₆ halocycloalkyl; nis 0, 1 or 2; and R^(A1), R^(B1), R^(A2), R^(B2), R^(A4) and R^(B4) areat each occurrence independently selected from the group consisting ofH, C₁₋₄ alkyl, and C₁₋₄ haloalkyl.
 34. A method of treatment of acondition mediated by the Wnt signalling pathway selected from the groupconsisting of esophageal squamous cell carcinoma, gastric cancer,glioblastomas, astrocytomas, retinoblastoma, osteosarcoma,chondosarcoma, Ewing's sarcoma, rhabdomysarcoma, Wilm's tumour, basalcell carcinoma, non-small cell lung cancer, brain tumour, hormonerefractory prostate cancer, prostate cancer, metastatic breast cancer,breast cancer, metastatic pancreatic cancer, pancreatic cancer,colorectal cancer, cervical cancer, head and neck squamous cellcarcinoma, and cancer of the head neck, wherein the method comprisesadministering to a patient in need thereof a therapeutic amount of acompound of claim 22 and a pharmaceutically acceptable excipient.
 35. Amethod of treatment of a condition mediated by the Wnt signallingpathway selected from the group consisting of skin fibrosis, idiopathicpulmonary fibrosis, renal interstitial fibrosis, liver fibrosis,proteinuria, kidney graft rejection, osteoarthritis, Parkinson'sdisease, cystoid macular edema, uveitis associated cystoid macularedema, retinopathy, diabetic retinopathy and retinopathy of prematurity,wherein the method comprises administering to a patient in need thereofa therapeutic amount of a compound of claim 22 and a pharmaceuticallyacceptable excipient.